The Neurokinins: Peptidomimetic Ligand Design and Therapeutic Applications

Charlène      Gadais; Steven        Ballet
doi:10.2174/0929867325666180913095918
Abstract

The neurokinins are indisputably essential neurotransmitters in numerous pathoand physiological events. Being widely distributed in the Central Nervous System (CNS) and peripheral tissues, their discovery rapidly promoted them to drugs targets. As a necessity for molecular tools to understand the biological role of this class, endogenous peptides and their receptors prompted the scientific community to design ligands displaying either agonist and antagonist activity at the three main neurokinin receptors, called NK1, NK2 and NK3. Several strategies were implemented for this purpose. With a preference to small non-peptidic ligands, many research groups invested efforts in synthesizing and evaluating a wide range of scaffolds, but only the NK1 antagonist Aprepitant (EMENDT) and its prodrug Fosaprepitant (IVEMENDT) have been approved by the Food Drug Administration (FDA) for the treatment of Chemotherapy-Induced and Post-Operative Nausea and Vomiting (CINV and PONV, respectively). While non-peptidic drugs showed limitations, especially in side effect control, peptidic and pseudopeptidic compounds progressively regained attention. Various strategies were implemented to modulate affinity, selectivity and activity of the newly designed ligands. Replacement of canonical amino acids, incorporation of conformational constraints, and fusion with non-peptidic moieties gave rise to families of ligands displaying individual or dual NK1, NK2 and NK3 antagonism, that ultimately were combined with non-neurokinin ligands (such as opioids) to target enhanced biological impact.
Keywords: Neurokinin, ligand, antagonist, peptidomimetic, small heterocyclic scaffold, drug design.
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[1] 
Maggi, C.A. The mammalian tachykinin receptors. Gen. Pharmacol.,  1995, 26(5), 911-944.
[http://dx.doi.org/10.1016/0306-3623(94)00292-U] [PMID: 7557266] 
[2] 
Severini, C.; Improta, G.; Falconieri-Erspamer, G.; Salvadori, S.; Erspamer, V. The tachykinin peptide family. Pharmacol. Rev.,  2002, 54(2), 285-322.
[http://dx.doi.org/10.1124/pr.54.2.285] [PMID: 12037144] 
[3] 
Euler, U.S.; Gaddum, J.H. An unidentified depressor substance in certain tissue ex-tracts. J. Physiol.,  1971, 72(1), 74-87.
[http://dx.doi.org/10.1038/newbio232086a0] [PMID: 5285346] 
[4] 
Chang, M.M.; Leeman, S.E.; Niall, H.D. Amino-acid sequence of substance P. Nat. New Biol.,  1971, 232(29), 86-87.
[http://dx.doi.org/10.1038/newbio232086a0] [PMID: 5285346] 
[5] 
Hökfelt, T.; Pernow, B.; Wahren, J. Substance P: a pioneer amongst neuropeptides. J. Intern. Med.,  2001, 249(1), 27-40.
[http://dx.doi.org/10.1046/j.0954-6820.2000.00773.x] [PMID: 11168782] 
[6] 
Kimura, S.; Okada, M.; Sugita, Y.; Kanazawa, I.; Munekata, E. Novel neuropeptides, neurokinin-alpha and neurokinin-beta isolated from porcine spinal-cord. Proc. Jpn. Acad., Ser. B, Phys. Biol. Sci.,  1983, 59(4), 101-104.
[http://dx.doi.org/10.2183/pjab.59.101] 
[7] 
Nawa, H.; Hirose, T.; Takashima, H.; Inayama, S.; Nakanishi, S. Nucleotide sequences of cloned cDNAs for two types of bovine brain substance P precursor. Nature,  1983, 306(5938), 32-36.
[http://dx.doi.org/10.1038/306032a0] [PMID: 6195531] 
[8] 
Nawa, H.; Doteuchi, M.; Igano, K.; Inouye, K.; Nakanishi, S. Substance K: a novel mammalian tachykinin that differs from substance P in its pharmacological profile. Life Sci.,  1984, 34(12), 1153-1160.
[http://dx.doi.org/10.1016/0024-3205(84)90087-0] [PMID: 6200746] 
[9] 
Kangawa, K.; Minamino, N.; Fukuda, A.; Matsuo, H. Neuromedin K: a novel mammalian tachykinin identified in porcine spinal cord. Biochem. Biophys. Res. Commun.,  1983, 114(2), 533-540.
[http://dx.doi.org/10.1016/0006-291X(83)90813-6] [PMID: 6576785] 
[10] 
Minamino, N.; Kangawa, K.; Fukuda, A.; Matsuo, H. Neuromedin L: a novel mammalian tachykinin identified in porcine spinal cord. Neuropeptides,  1984, 4(2), 157-166.
[http://dx.doi.org/10.1016/0143-4179(84)90126-4] [PMID: 6144073] 
[11] 
Tatemoto, K.; Lundberg, J.M.; Jörnvall, H.; Mutt, V. Neuropeptide K: isolation, structure and biological activities of a novel brain tachykinin. Biochem. Biophys. Res. Commun.,  1985, 128(2), 947-953.
[http://dx.doi.org/10.1016/0006-291X(85)90138-X] [PMID: 2581573] 
[12] 
Kage, R.; McGregor, G.P.; Thim, L.; Conlon, J.M. Neuropeptide-gamma: a peptide isolated from rabbit intestine that is derived from gamma-preprotachykinin. J. Neurochem.,  1988, 50(5), 1412-1417.
[http://dx.doi.org/10.1111/j.1471-4159.1988.tb03024.x] [PMID: 2834512] 
[13] 
Zhang, Y.; Lu, L.; Furlonger, C.; Wu, G.E.; Paige, C.J. Hemokinin is a hematopoietic-specific tachykinin that regulates B lymphopoiesis. Nat. Immunol.,  2000, 1(5), 392-397.
[http://dx.doi.org/10.1038/80826] [PMID: 11062498] 
[14] 
Borbély, É.; Helyes, Z. Role of hemokinin-1 in health and disease. Neuropeptides,  2017, 64, 9-17.
[http://dx.doi.org/10.1016/j.npep.2016.12.003] [PMID: 27993375] 
[15] 
Pennefather, J.N.; Lecci, A.; Candenas, M.L.; Patak, E.; Pinto, F.M.; Maggi, C.A. Tachykinins and tachykinin receptors: a growing family. Life Sci.,  2004, 74(12), 1445-1463.
[http://dx.doi.org/10.1016/j.lfs.2003.09.039] [PMID: 14729395] 
[16] 
Rosenbaum, D.M.; Rasmussen, S.G.F.; Kobilka, B.K. The structure and function of G-protein-coupled receptors. Nature,  2009, 459(7245), 356-363.
[http://dx.doi.org/10.1038/nature08144] [PMID: 19458711] 
[17] 
Garcia-Recio, S.; Gascón, P. Biological and pharmacological aspects of the NK1-receptor. BioMed Res. Int.,  2015, 2015495704
[http://dx.doi.org/10.1155/2015/495704] [PMID: 26421291] 
[18] 
Page, N.M. New challenges in the study of the mammalian tachykinins. Peptides,  2005, 26(8), 1356-1368.
[http://dx.doi.org/10.1016/j.peptides.2005.03.030] [PMID: 16042976] 
[19] 
Shimizu, Y.; Matsuyama, H.; Shiina, T.; Takewaki, T.; Furness, J.B. Tachykinins and their functions in the gastrointestinal tract. Cell. Mol. Life Sci.,  2008, 65(2), 295-311.
[http://dx.doi.org/10.1007/s00018-007-7148-1] [PMID: 17952369] 
[20] 
Maggi, C.A. Tachykinin receptors and airway pathophysiology. Eur. Respir. J.,  1993, 6(5), 735-742.
[PMID: 8390944] 
[21] 
Nassini, R.; Materazzi, S.; De Siena, G.; De Cesaris, F.; Geppetti, P. Transient receptor potential channels as novel drug targets in respiratory diseases. Curr. Opin. Investig. Drugs,  2010, 11(5), 535-542.
[PMID: 20419599] 
[22] 
Candenas, L.; Lecci, A.; Pinto, F.M.; Patak, E.; Maggi, C.A.; Pennefather, J.N. Tachykinins and tachykinin receptors: effects in the genitourinary tract. Life Sci.,  2005, 76(8), 835-862.
[http://dx.doi.org/10.1016/j.lfs.2004.10.004] [PMID: 15589963] 
[23] 
Johnson, M.B.; Young, A.D.; Marriott, I. The therapeutic potential of targeting substance P/NK-1R interactions in inflammatory CNS disorders. Front. Cell. Neurosci.,  2017, 10(296), 296.
[http://dx.doi.org/10.3389/fncel.2016.00296] [PMID: 28101005] 
[24] 
Douglas, S.D.; Leeman, S.E. Neurokinin-1 receptor: functional significance in the immune system in reference to selected infections and inflammation. Ann. N. Y. Acad. Sci.,  2011, 1217, 83-95.
[http://dx.doi.org/10.1111/j.1749-6632.2010.05826.x] 
[25] 
Muñoz, M.; Coveñas, R. Involvement of substance P and the NK-1 receptor in cancer progression. Peptides,  2013, 48, 1-9.
[http://dx.doi.org/10.1016/j.peptides.2013.07.024] [PMID: 23933301] 
[26] 
Mistrova, E.; Kruzliak, P.; Chottova Dvorakova, M. Role of substance P in the cardiovascular system. Neuropeptides,  2016, 58, 41-51.
[http://dx.doi.org/10.1016/j.npep.2015.12.005] [PMID: 26706184] 
[27] 
Walsh, D.A.F.; McWilliams, D. Tachykinins and the cardiovascular system. Curr. Drug Targets,  2006, 7(8), 1031-1042.
[http://dx.doi.org/10.2174/138945006778019291] [PMID: 16918331] 
[28] 
Kaczyńska, K.; Jampolska, M.; Szereda-Przestaszewska, M. The role of vagal pathway and NK1 and NK2 receptors in cardiovascular and respiratory effects of neurokinin A. Clin. Exp. Pharmacol. Physiol.,  2016, 43(9), 818-824.
[http://dx.doi.org/10.1111/1440-1681.12594] [PMID: 27199181] 
[29] 
Dehlin, H.M.; Levick, S.P. Substance P in heart failure: the good and the bad. Int. J. Cardiol.,  2014, 170(3), 270-277.
[http://dx.doi.org/10.1016/j.ijcard.2013.11.010] [PMID: 24286592] 
[30] 
Steinhoff, M.S.; von Mentzer, B.; Geppetti, P.; Pothoulakis, C.; Bunnett, N.W. Tachykinins and their receptors: contributions to physiological control and the mechanisms of disease. Physiol. Rev.,  2014, 94(1), 265-301.
[http://dx.doi.org/10.1152/physrev.00031.2013] [PMID: 24382888] 
[31] 
Yang, Y.; Yan, M.; Zhang, H.; Wang, X. Substance P participates in immune-mediated hepatic injury induced by concanavalin A in mice and stimulates cytokine synthesis in Kupffer cells. Exp. Ther. Med.,  2013, 6(2), 459-464.
[http://dx.doi.org/10.3892/etm.2013.1152] [PMID: 24137208] 
[32] 
Mashaghi, A.; Marmalidou, A.; Tehrani, M.; Grace, P.M.; Pothoulakis, C.; Dana, R. Neuropeptide substance P and the immune response. Cell. Mol. Life Sci.,  2016, 73(22), 4249-4264.
[http://dx.doi.org/10.1007/s00018-016-2293-z] [PMID: 27314883] 
[33] 
Liu, K.; Castillo, M.D.; Murthy, R.G.; Patel, N.; Rameshwar, P. Tachykinins and hematopoiesis. Clin. Chim. Acta,  2007, 385(1-2), 28-34.
[http://dx.doi.org/10.1016/j.cca.2007.07.008] [PMID: 17698052] 
[34] 
Rosso, M.; Muñoz, M.; Berger, M. The role of neurokinin-1 receptor in the microenvironment of inflammation and cancer. ScientificWorldJournal,  2012, 2012381434
[PMID: 22545017] 
[35] 
Leal, E.C.; Carvalho, E.; Tellechea, A.; Kafanas, A.; Tecilazich, F.; Kearney, C.; Kuchibhotla, S.; Auster, M.E.; Kokkotou, E.; Mooney, D.J.; LoGerfo, F.W.; Pradhan-Nabzdyk, L.; Veves, A. Substance P promotes wound healing in diabetes by modulating inflammation and macrophage phenotype. Am. J. Pathol.,  2015, 185(6), 1638-1648.
[http://dx.doi.org/10.1016/j.ajpath.2015.02.011] [PMID: 25871534] 
[36] 
Ni, T.; Jia, Z.G.; Gao, F.H.; Fang, Y.; Yu, W.R.; Zhang, X.; Yao, M. Substance P induces monocyte chemoattractant protein-1 production in skin fibroblasts from genetically-diabetic mice via activation of NF-kappa B. Int. J. Clin. Exp. Pathol.,  2016, 9(7), 6683-6693.
[37] 
Słoniecka, M.; Le Roux, S.; Zhou, Q.; Danielson, P. Substance P enhances keratocyte migration and neutrophil recruitment through interleukin-8. Mol. Pharmacol.,  2016, 89(2), 215-225.
[http://dx.doi.org/10.1124/mol.115.101014] [PMID: 26646648] 
[38] 
Suvas, S. Role of substance P neuropeptide in inflammation, wound healing, and tissue homeostasis. J. Immunol.,  2017, 199(5), 1543-1552.
[http://dx.doi.org/10.4049/jimmunol.1601751] [PMID: 28827386] 
[39] 
Chiu, I.M.; von Hehn, C.A.; Woolf, C.J. Neurogenic inflammation and the peripheral nervous system in host defense and immunopathology. Nat. Neurosci.,  2012, 15(8), 1063-1067.
[http://dx.doi.org/10.1038/nn.3144] [PMID: 22837035] 
[40] 
Malhotra, R. Understanding migraine: Potential role of neurogenic inflammation. Ann. Indian Acad. Neurol.,  2016, 19(2), 175-182.
[http://dx.doi.org/10.4103/0972-2327.182302] [PMID: 27293326] 
[41] 
Muñoz, M.; Rosso, M.; Coveñas, R. A new frontier in the treatment of cancer: NK-1 receptor antagonists. Curr. Med. Chem.,  2010, 17(6), 504-516.
[http://dx.doi.org/10.2174/092986710790416308] [PMID: 20015033] 
[42] 
Muñoz, M.; Rosso, M. The NK-1 receptor antagonist aprepitant as a broad spectrum antitumor drug. Invest. New Drugs,  2010, 28(2), 187-193.
[http://dx.doi.org/10.1007/s10637-009-9218-8] [PMID: 19148578] 
[43] 
Muñoz, M.; Rosso, M.; Coveñas, R. The NK-1 receptor: a new target in cancer therapy. Curr. Drug Targets,  2011, 12(6), 909-921.
[http://dx.doi.org/10.2174/138945011795528796] [PMID: 21226668] 
[44] 
Muñoz, M.; Martinez-Armesto, J.; Coveñas, R. NK-1 receptor antagonists as antitumor drugs: a survey of the literature from 2000 to 2011. Expert Opin. Ther. Pat.,  2012, 22(7), 735-746.
[http://dx.doi.org/10.1517/13543776.2012.697153] [PMID: 22697287] 
[45] 
Munoz, M.; Covenas, R. NK-1 receptor antagonists: a new generation of anticancer drugs. Mini Rev. Med. Chem.,  2012, 12(7), 593-599.
[http://dx.doi.org/10.2174/138955712800626692] [PMID: 22512565] 
[46] 
Muñoz, M.; González-Ortega, A.; Rosso, M.; Robles-Frias, M.J.; Carranza, A.; Salinas-Martín, M.V.; Coveñas, R. The substance P/neurokinin-1 receptor system in lung cancer: focus on the antitumor action of neurokinin-1 receptor antagonists. Peptides,  2012, 38(2), 318-325.
[http://dx.doi.org/10.1016/j.peptides.2012.09.024] [PMID: 23026680] 
[47] 
Coveñas, R.; Muñoz, M. Cancer progression and substance P. Histol. Histopathol.,  2014, 29(7), 881-890.
[http://dx.doi.org/10.14670/HH-29.881] [PMID: 24535838] 
[48] 
Muñoz, M.; González-Ortega, A.; Salinas-Martín, M.V.; Carranza, A.; Garcia-Recio, S.; Almendro, V.; Coveñas, R. The neurokinin-1 receptor antagonist aprepitant is a promising candidate for the treatment of breast cancer. Int. J. Oncol.,  2014, 45(4), 1658-1672.
[http://dx.doi.org/10.3892/ijo.2014.2565] [PMID: 25175857] 
[49] 
Muñoz, M.; Coveñas, R. Neurokinin-1 receptor antagonists as antitumor drugs in gastrointestinal cancer: A new approach. Saudi J. Gastroenterol.,  2016, 22(4), 260-268.
[http://dx.doi.org/10.4103/1319-3767.187601] [PMID: 27488320] 
[50] 
Muñoz, M.; Coveñas, R. NK-1 receptor antagonists: a new paradigm in pharmacological therapy. Curr. Med. Chem.,  2011, 18(12), 1820-1831.
[http://dx.doi.org/10.2174/092986711795496746] [PMID: 21466470] 
[51] 
Vink, R.; van den Heuvel, C. Substance P antagonists as a therapeutic approach to improving outcome following traumatic brain injury. Neurotherapeutics,  2010, 7(1), 74-80.
[http://dx.doi.org/10.1016/j.nurt.2009.10.018] [PMID: 20129499] 
[52] 
Albert, J.S. Neurokinin antagonists and their potential role in treating depression and other stress disorders. Expert Opin. Ther. Pat.,  2004, 14(10), 1421-1433.
[http://dx.doi.org/10.1517/13543776.14.10.1421] 
[53] 
Muñoz, M.; Coveñas, R. Involvement of substance P and the NK-1 receptor in human pathology. Amino Acids,  2014, 46(7), 1727-1750.
[http://dx.doi.org/10.1007/s00726-014-1736-9] [PMID: 24705689] 
[54] 
Degnan, A.P.; Tora, G.O.; Han, Y.; Rajamani, R.; Bertekap, R.; Krause, R.; Davis, C.D.; Hu, J.; Morgan, D.; Taylor, S.J.; Krause, K.; Li, Y.W.; Mattson, G.; Cunningham, M.A.; Taber, M.T.; Lodge, N.J.; Bronson, J.J.; Gillman, K.W.; Macor, J.E. Biaryls as potent, tunable dual neurokinin 1 receptor antagonists and serotonin transporter inhibitors. Bioorg. Med. Chem. Lett.,  2015, 25(15), 3039-3043.
[http://dx.doi.org/10.1016/j.bmcl.2015.04.098] [PMID: 26048800] 
[55] 
Degnan, A.P.; Tora, G.O.; Huang, H.; Conlon, D.A.; Davis, C.D.; Hanumegowda, U.M.; Hou, X.; Hsiao, Y.; Hu, J.; Krause, R.; Li, Y.W.; Newton, A.E.; Pieschl, R.L.; Raybon, J.; Rosner, T.; Sun, J.H.; Taber, M.T.; Taylor, S.J.; Wong, M.K.; Zhang, H.; Lodge, N.J.; Bronson, J.J.; Macor, J.E.; Gillman, K.W. Discovery of indazoles as potent, orally active dual neurokinin 1 receptor antagonists and serotonin transporter inhibitors for the treatment of depression. ACS Chem. Neurosci.,  2016, 7(12), 1635-1640.
[http://dx.doi.org/10.1021/acschemneuro.6b00337] [PMID: 27744678] 
[56] 
Di Maio, M.; Baratelli, C.; Bironzo, P.; Vignani, F.; Bria, E.; Sperti, E.; Marcato, M.; Roila, F. Efficacy of neurokinin-1 receptor antagonists in the prevention of Chemotherapy-Induced Nausea and Vomiting (CINV) in patients receiving carboplatin-based chemotherapy: a systematic review and meta-analysis. Ann. Oncol.,  2017, 28(Suppl. 6), vi90.
[http://dx.doi.org/10.1093/annonc/mdx435.005] [PMID: 31962872] 
[57] 
Rapoport, B.; Smit, T. Clinical pharmacology of neurokinin-1 receptor antagonists for the treatment of nausea and vomiting associated with chemotherapy. Expert Opin. Drug Saf.,  2017, 16(6), 697-710.
[http://dx.doi.org/10.1080/14740338.2017.1325868] [PMID: 28460548] 
[58] 
Zhang, Y.X.; Yang, Y.P.; Zhang, Z.H.; Fang, W.F.; Kang, S.Y.; Luo, Y.L.; Sheng, J.; Zhan, J.H.; Hong, S.D.; Huang, Y.; Zhou, N.N.; Zhao, H.Y.; Zhang, L. Neurokinin-1 receptor antagonist-based triple regimens in preventing chemotherapy-induced nausea and vomiting: a network meta-analysis. J. Natl. Cancer Inst.,  2016, 109(2)djw217
[http://dx.doi.org/10.1093/jnci/djw217] [PMID: 27795228] 
[59] 
Jones, S.; Gibbins, J.M. The neurokinin 1 receptor: a potential new target for anti-platelet therapy? Curr. Opin. Pharmacol.,  2008, 8(2), 114-119.
[http://dx.doi.org/10.1016/j.coph.2008.01.004] [PMID: 18296119] 
[60] 
Mantyh, P.W.; DeMaster, E.; Malhotra, A.; Ghilardi, J.R.; Rogers, S.D.; Mantyh, C.R.; Liu, H.; Basbaum, A.I.; Vigna, S.R.; Maggio, J.E.; Simone, D.A. Receptor endocytosis and dendrite reshaping in spinal neurons after somatosensory stimulation. Science,  1995, 268(5217), 1629-1632.
[http://dx.doi.org/10.1126/science.7539937] [PMID: 7539937] 
[61] 
Trafton, J.A.; Abbadie, C.; Marchand, S.; Mantyh, P.W.; Basbaum, A.I. Spinal opioid analgesia: how critical is the regulation of substance P signaling? J. Neurosci.,  1999, 19(21), 9642-9653.
[http://dx.doi.org/10.1523/JNEUROSCI.19-21-09642.1999] [PMID: 10531466] 
[62] 
Borsook, D.; Upadhyay, J.; Klimas, M.; Schwarz, A.J.; Coimbra, A.; Baumgartner, R.; George, E.; Potter, W.Z.; Large, T.; Bleakman, D.; Evelhoch, J.; Iyengar, S.; Becerra, L.; Hargreaves, R.J. Decision-making using fMRI in clinical drug development: revisiting NK-1 receptor antagonists for pain. Drug Discov. Today,  2012, 17(17-18), 964-973.
[http://dx.doi.org/10.1016/j.drudis.2012.05.004] [PMID: 22579743] 
[63] 
Johansson, A. Recent developments in the medicinal chemistry of NK2 receptor antagonists. Curr. Top. Med. Chem.,  2003, 3(12), 1436-1445.
[http://dx.doi.org/10.2174/1568026033451835] [PMID: 12871174] 
[64] 
Tramontana, M.; Maggi, C.A.; Evangelista, S. Spasmolytic effect of the NK2-receptor-selective antagonist MEN 10,627 in rat small intestine. Jpn. J. Pharmacol.,  1994, 65(3), 281-283.
[http://dx.doi.org/10.1254/jjp.65.281] [PMID: 7799529] 
[65] 
Holzer-Petsche, U. Tachykinin receptors in gastrointestinal motility. Regul. Pept.,  1995, 57(1), 19-42.
[http://dx.doi.org/10.1016/0167-0115(95)00019-8] [PMID: 7644701] 
[66] 
Hällgren, A.; Flemström, G.; Hellström, P.M.; Lördal, M.; Hellgren, S.; Nylander, O. Neurokinin A increases duodenal mucosal permeability, bicarbonate secretion, and fluid output in the rat. Am. J. Physiol.,  1997, 273(5), G1077-G1086.
[http://dx.doi.org/10.1152/ajpgi.1997.273.5.G1077] [PMID: 9374705] 
[67] 
Lecci, A.; Capriati, A.; Maggi, C.A. Tachykinin NK2 receptor antagonists for the treatment of irritable bowel syndrome. Br. J. Pharmacol.,  2004, 141(8), 1249-1263.
[http://dx.doi.org/10.1038/sj.bjp.0705751] [PMID: 15037522] 
[68] 
Patacchini, R.; Santicioli, P.; Zagorodnyuk, V.; Lazzeri, M.; Turini, D.; Maggi, C.A. Excitatory motor and electrical effects produced by tachykinins in the human and guinea-pig isolated ureter and guinea-pig renal pelvis. Br. J. Pharmacol.,  1998, 125(5), 987-996.
[http://dx.doi.org/10.1038/sj.bjp.0702147] [PMID: 9846636] 
[69] 
Kojima, S.; Ikeda, M.; Kamikawa, Y. Further investigation into the mechanism of tachykinin NK(2) receptor-triggered serotonin release from guinea-pig proximal colon. J. Pharmacol. Sci.,  2009, 110(1), 122-126.
[http://dx.doi.org/10.1254/jphs.09032SC] [PMID: 19423952] 
[70] 
Kojima, S.; Tohei, A.; Ikeda, M.; Anzai, N. An endogenous tachykinergic NK2/NK3 receptor cascade system controlling the release of serotonin from colonic mucosa. Curr. Neuropharmacol.,  2015, 13(6), 830-835.
[http://dx.doi.org/10.2174/1570159X13666150825220524] [PMID: 26630961] 
[71] 
Julia, V.; Morteau, O.; Buéno, L. Involvement of neurokinin 1 and 2 receptors in viscerosensitive response to rectal distension in rats. Gastroenterology,  1994, 107(1), 94-102.
[http://dx.doi.org/10.1016/0016-5085(94)90065-5] [PMID: 7517374] 
[72] 
Langlois, X.; te Riele, P.; Wintmolders, C.; Leysen, J.E.; Jurzak, M. Use of the beta-imager for rapid ex vivo autoradiography exemplified with central nervous system penetrating neurokinin 3 antagonists. J. Pharmacol. Exp. Ther.,  2001, 299(2), 712-717.
[PMID: 11602685] 
[73] 
Harrison, P.J. The neuropathology of schizophrenia. A critical review of the data and their interpretation. Brain,  1999, 122(Pt 4), 593-624.
[http://dx.doi.org/10.1093/brain/122.4.593] [PMID: 10219775] 
[74] 
Dawson, L.A.; Smith, P.W. Therapeutic utility of NK3 receptor antagonists for the treatment of schizophrenia. Curr. Pharm. Des.,  2010, 16(3), 344-357.
[http://dx.doi.org/10.2174/138161210790170067] [PMID: 20109143] 
[75] 
Simonsen, K.B.; Juhl, K.; Steiniger-Brach, B.; Nielsen, S.M. Novel NK(3) receptor antagonists for the treatment of schizophrenia and other CNS indications. Curr. Opin. Drug Discov. Devel.,  2010, 13(4), 379-388.
[PMID: 20597024] 
[76] 
Litman, R.E.; Smith, M.A.; Desai, D.G.; Simpson, T.; Sweitzer, D.; Kanes, S.J. The selective neurokinin 3 antagonist AZD2624 does not improve symptoms or cognition in schizophrenia: a proof-of-principle study. J. Clin. Psychopharmacol.,  2014, 34(2), 199-204.
[http://dx.doi.org/10.1097/JCP.0000000000000071] [PMID: 24525659] 
[77] 
Primi, M.C.; Maltarollo, V.G.; Magalhães, J.G.; de Sá, M.M.; Rangel-Yagui, C.O.; Trossini, G.H.G. Convergent QSAR studies on a series of NK3 receptor antagonists for schizophrenia treatment. J. Enzyme Inhib. Med. Chem.,  2016, 31(2), 283-294.
[http://dx.doi.org/10.3109/14756366.2015.1021250] [PMID: 25856571] 
[78] 
Catalani, M.P.; Alvaro, G.; Bernasconi, G.; Bettini, E.; Bromidge, S.M.; Heer, J.; Tedesco, G.; Tommasi, S. Identification of novel NK1/NK3 dual antagonists for the potential treatment of schizophrenia. Bioorg. Med. Chem. Lett.,  2011, 21(22), 6899-6904.
[http://dx.doi.org/10.1016/j.bmcl.2011.07.116] [PMID: 21974957] 
[79] 
Spooren, W.; Riemer, C.; Meltzer, H. Opinion: NK3 receptor antagonists: the next generation of antipsychotics? Nat. Rev. Drug Discov.,  2005, 4(12), 967-975.
[http://dx.doi.org/10.1038/nrd1905] [PMID: 16341062] 
[80] 
Fraser, G.L.; Hoveyda, H.R.; Clarke, I.J.; Ramaswamy, S.; Plant, T.M.; Rose, C.; Millar, R.P. The NK3 receptor antagonist ESN364 interrupts pulsatile LH secretion and moderates levels of ovarian hormones throughout the menstrual cycle. Endocrinology,  2015, 156(11), 4214-4225.
[http://dx.doi.org/10.1210/en.2015-1409] [PMID: 26305889] 
[81] 
Hoveyda, H.R.; Fraser, G.L.; Dutheuil, G.; El Bousmaqui, M.; Korac, J.; Lenoir, F.; Lapin, A.; Noël, S. Optimization of novel antagonists to the neurokinin-3 receptor for the treatment of sex-hormone disorders (part II). ACS Med. Chem. Lett.,  2015, 6(7), 736-740.
[http://dx.doi.org/10.1021/acsmedchemlett.5b00117] [PMID: 26191358] 
[82] 
Hoveyda, H.R.; Fraser, G.L.; Roy, M.O.; Dutheuil, G.; Batt, F.; El Bousmaqui, M.; Korac, J.; Lenoir, F.; Lapin, A.; Noël, S.; Blanc, S. Discovery and optimization of novel antagonists to the human neurokinin-3 receptor for the treatment of sex-hormone disorders (Part I). J. Med. Chem.,  2015, 58(7), 3060-3082.
[http://dx.doi.org/10.1021/jm5017413] [PMID: 25738882] 
[83] 
Fraser, G.L.; Ramael, S.; Hoveyda, H.R.; Gheyle, L.; Combalbert, J. The NK3 receptor antagonist ESN364 suppresses sex hormones in men and women. J. Clin. Endocrinol. Metab.,  2016, 101(2), 417-426.
[http://dx.doi.org/10.1210/jc.2015-3621] [PMID: 26653113] 
[84] 
Schooling, C.M. Tachykinin neurokinin 3 receptor antagonists: a new treatment for cardiovascular disease? Lancet,  2017, 390(10095), 709-711.
[http://dx.doi.org/10.1016/S0140-6736(16)31648-8] [PMID: 28359648] 
[85] 
Schmid, G.; Carità, F.; Bonanno, G.; Raiteri, M. NK-3 receptors mediate enhancement of substance P release from capsaicin-sensitive spinal cord afferent terminals. Br. J. Pharmacol.,  1998, 125(4), 621-626.
[http://dx.doi.org/10.1038/sj.bjp.0702093] [PMID: 9831894] 
[86] 
Pintér, E.; Pozsgai, G.; Hajna, Z.; Helyes, Z.; Szolcsányi, J. Neuropeptide receptors as potential drug targets in the treatment of inflammatory conditions. Br. J. Clin. Pharmacol.,  2014, 77(1), 5-20.
[http://dx.doi.org/10.1111/bcp.12097] [PMID: 23432438] 
[87] 
Zaratin, P.; Angelici, O.; Clarke, G.D.; Schmid, G.; Raiteri, M.; Carità, F.; Bonanno, G. NK3 receptor blockade prevents hyperalgesia and the associated spinal cord substance P release in monoarthritic rats. Neuropharmacology,  2000, 39(1), 141-149.
[http://dx.doi.org/10.1016/S0028-3908(99)00087-8] [PMID: 10665827] 
[88] 
Linden, D.R.; Seybold, V.S. Spinal neurokinin3 receptors mediate thermal but not mechanical hyperalgesia via nitric oxide. Pain,  1999, 80(1-2), 309-317.
[http://dx.doi.org/10.1016/S0304-3959(98)00222-X] [PMID: 10204744] 
[89] 
Julia, V.; Su, X.; Buéno, L.; Gebhart, G.F. Role of neurokinin 3 receptors on responses to colorectal distention in the rat: electrophysiological and behavioral studies. Gastroenterology,  1999, 116(5), 1124-1131.
[http://dx.doi.org/10.1016/S0016-5085(99)70015-6] [PMID: 10220504] 
[90] 
Houghton, L.A.; Cremonini, F.; Camilleri, M.; Busciglio, I.; Fell, C.; Cox, V.; Alpers, D.H.; Dewit, O.E.; Dukes, G.E.; Gray, E.; Lea, R.; Zinsmeister, A.R.; Whorwell, P.J. Effect of the NK(3) receptor antagonist, talnetant, on rectal sensory function and compliance in healthy humans. Neurogastroenterol. Motil.,  2007, 19(9), 732-743.
[http://dx.doi.org/10.1111/j.1365-2982.2007.00934.x] [PMID: 17727393] 
[91] 
Almeida, T.A.; Rojo, J.; Nieto, P.M.; Pinto, F.M.; Hernandez, M.; Martín, J.D.; Candenas, M.L. Tachykinins and tachykinin receptors: structure and activity relationships. Curr. Med. Chem.,  2004, 11(15), 2045-2081.
[http://dx.doi.org/10.2174/0929867043364748] [PMID: 15279567] 
[92] 
Lavielle, S.; Chassaing, G.; Loeuillet, D.; Convert, O.; Torrens, Y.; Beaujouan, J.C.; Saffroy, M.; Petitet, F.; Bergström, L.; Glowinski, J. Selective agonists of tachykinin binding sites. Fundam. Clin. Pharmacol.,  1990, 4(3), 257-268.
[http://dx.doi.org/10.1111/j.1472-8206.1990.tb00493.x] [PMID: 2165464] 
[93] 
Regoli, D.; Nantel, F. Pharmacology of neurokinin receptors. Biopolymers,  1991, 31(6), 777-783.
[http://dx.doi.org/10.1002/bip.360310623] [PMID: 1718474] 
[94] 
Drapeau, G.; D’Orléans-Juste, P.; Dion, S.; Rhaleb, N.E.; Rouissi, N.E.; Regoli, D. Selective agonists for substance P and neurokinin receptors. Neuropeptides,  1987, 10(1), 43-54.
[http://dx.doi.org/10.1016/0143-4179(87)90088-6] [PMID: 2444902] 
[95] 
Warner, F.J.; Miller, R.C.; Burcher, E. Structure-activity relationship of neurokinin A(4-10) at the human tachykinin NK(2) receptor: the effect of amino acid substitutions on receptor affinity and function. Biochem. Pharmacol.,  2002, 63(12), 2181-2186.
[http://dx.doi.org/10.1016/S0006-2952(02)01014-6] [PMID: 12110377] 
[96] 
Convert, O.; Duplaa, H.; Lavielle, S.; Chassaing, G. Influence of the replacement of amino acid by its D-enantiomer in the sequence of substance P. 2. Conformational analysis by NMR and energy calculations. Neuropeptides,  1991, 19(4), 259-270.
[http://dx.doi.org/10.1016/0143-4179(91)90093-X] [PMID: 1717877] 
[97] 
Folkers, K.; Hörig, J.; Rosell, S.; Björkroth, U. Chemical design of antagonists of substance P. Acta Physiol. Scand.,  1981, 111(4), 505-506.
[http://dx.doi.org/10.1111/j.1748-1716.1981.tb06771.x] [PMID: 6171138] 
[98] 
Hökfelt, T.; Vincent, S.; Hellsten, L.; Rosell, S.; Folkers, K.; Markey, K.; Goldstein, M.; Cuello, C. Immunohistochemical evidence for a “neurotoxic” action of (D-Pro2, D-Trp7,9)-substance P, an analogue with substance P antagonistic activity. Acta Physiol. Scand.,  1981, 113(4), 571-573.
[http://dx.doi.org/10.1111/j.1748-1716.1981.tb06943.x] [PMID: 6182746] 
[99] 
Leander, S.; Håkanson, R.; Rosell, S.; Folkers, K.; Sundler, F.; Tornqvist, K. A specific substance P antagonist blocks smooth muscle contractions induced by non-cholinergic, non-adrenergic nerve stimulation. Nature,  1981, 294(5840), 467-469.
[http://dx.doi.org/10.1038/294467a0] [PMID: 6171733] 
[100] 
Rosell, S.; Olgart, L.; Gazelius, B.; Panopoulos, P.; Folkers, K.; Hörig, J. Inhibition of antidromic and substance P-induced vasodilatation by a substance P antagonist. Acta Physiol. Scand.,  1981, 111(3), 381-382.
[http://dx.doi.org/10.1111/j.1748-1716.1981.tb06752.x] [PMID: 6171999] 
[101] 
Svensson, T.H.; Engberg, G.; Rosell, S.; Folkers, K. Specific antagonism of substance-P induced excitation of locus coeruleus neurons by (D-Pro2, D-Trp7,9)-SP. Acta Pharmacol. Toxicol. (Copenh.),  1981, 49, 42-42.
[102] 
Engberg, G.; Svensson, T.H.; Rosell, S.; Folkders, K. A synthetic peptide as an antagonist of substance P. Nature,  1981, 293(5829), 222-223.
[http://dx.doi.org/10.1038/293222a0] [PMID: 6168917] 
[103] 
Dutta, A.S.; Gormley, J.J.; Graham, A.S.; Briggs, I.; Growcott, J.W.; Jamieson, A. Analogues of substance P. Peptides containing D-amino acid residues in various positions of substance P and displaying agonist or receptor selective antagonist effects. J. Med. Chem.,  1986, 29(7), 1163-1171.
[http://dx.doi.org/10.1021/jm00157a008] [PMID: 2433442] 
[104] 
Dutta, A.S.; Gormley, J.J.; Graham, A.S.; Briggs, I.; Growcott, J.W.; Jamieson, A. Antagonists of substance P. Further modifications of substance P antagonists obtained by replacing either positions 7, 9 or 7, 8 and 11 of SP with D-amino acid residues. J. Med. Chem.,  1986, 29(7), 1171-1178.
[http://dx.doi.org/10.1021/jm00157a009] [PMID: 2433443] 
[105] 
Rovero, P.; Pestellini, V.; Maggi, C.A.; Patacchini, R.; Regoli, D.; Giachetti, A. A highly selective NK-2 tachykinin receptor antagonist containing D-tryptophan. Eur. J. Pharmacol.,  1990, 175(1), 113-115.
[http://dx.doi.org/10.1016/0014-2999(90)90161-X] [PMID: 2157594] 
[106] 
Maggi, C.A.; Giuliani, S.; Ballati, L.; Lecci, A.; Manzini, S.; Patacchini, R.; Renzetti, A.R.; Rovero, P.; Quartara, L.; Giachetti, A. In vivo evidence for tachykininergic transmission using a new NK-2 receptor-selective antagonist, MEN 10,376. J. Pharmacol. Exp. Ther.,  1991, 257(3), 1172-1178.
[PMID: 1710662] 
[107] 
Rovero, P.; Astolfi, M.; Renzetti, A.R.; Patacchini, R.; Giachetti, A.; Maggi, C.A. Role of D-tryptophan for affinity of MEN 10207 tachykinin antagonist at NK2 receptors. Peptides,  1991, 12(5), 1015-1018.
[http://dx.doi.org/10.1016/0196-9781(91)90053-R] [PMID: 1666180] 
[108] 
Whitehead, T.L.; McNair, S.D.; Hadden, C.E.; Young, J.K.; Hicks, R.P. Membrane-induced secondary structures of neuropeptides: a comparison of the solution conformations adopted by agonists and antagonists of the mammalian tachykinin NK1 receptor. J. Med. Chem.,  1998, 41(9), 1497-1506.
[http://dx.doi.org/10.1021/jm970789x] [PMID: 9554882] 
[109] 
Prabhu, A.; Malde, A.; Coutinho, E.; Srivastava, S. Solution conformation of Substance P antagonists-[D-Arg1, D-Trp7,9, Leu11]-SP, [D-Arg1, D-Pro2, D-Trp7,9, Leu11]-SP and [D-Pro2, D-Trp7,9]-SP by CD, NMR and MD simulations. Peptides,  2005, 26(5), 875-885.
[http://dx.doi.org/10.1016/j.peptides.2004.12.001] [PMID: 15808918] 
[110] 
Folkers, K.; Håkanson, R.; Hörig, J.; Xu, J.C.; Leander, S. Biological evaluation of substance P antagonists. Br. J. Pharmacol.,  1984, 83(2), 449-456.
[http://dx.doi.org/10.1111/j.1476-5381.1984.tb16506.x] [PMID: 6207886] 
[111] 
Folkers, K.; Feng, D.M.; Asano, N.; Håkanson, R.; Weisenfeld-Hallin, Z.; Leander, S. Spantide II, an effective tachykinin antagonist having high potency and negligible neurotoxicity. Proc. Natl. Acad. Sci. USA,  1990, 87(12), 4833-4835.
[http://dx.doi.org/10.1073/pnas.87.12.4833] [PMID: 1693780] 
[112] 
Ljungqvist, A.; Feng, D.M.; Hook, W.; Shen, Z.X.; Bowers, C.; Folkers, K. Antide and related antagonists of luteinizing hormone release with long action and oral activity. Proc. Natl. Acad. Sci. USA,  1988, 85(21), 8236-8240.
[http://dx.doi.org/10.1073/pnas.85.21.8236] [PMID: 2460863] 
[113] 
Folkers, K.; Hakanson, R.; Feng, D.M.; Xu, J.C.; Janecka, A.; Wang, Z.Y. Spantide III, a superior tachykinin antagonist with high potency and negligible neurotoxicity. Amino Acids,  1993, 5(2), 233-238.
[http://dx.doi.org/10.1007/BF00805985] [PMID: 24190666] 
[114] 
Sagan, S.; Milcent, T.; Ponsinet, R.; Convert, O.; Tasseau, O.; Chassaing, G.; Lavielle, S.; Lequin, O. Structural and biological effects of a beta2- or beta3-amino acid insertion in a peptide. Eur. J. Biochem.,  2003, 270(5), 939-949.
[http://dx.doi.org/10.1046/j.1432-1033.2003.03456.x] [PMID: 12603327] 
[115] 
Drapeau, G.; Rouissi, N.; Nantel, F.; Rhaleb, N.E.; Tousignant, C.; Regoli, D. Antagonists for the neurokinin NK-3 receptor evaluated in selective receptor systems. Regul. Pept.,  1990, 31(2), 125-135.
[http://dx.doi.org/10.1016/0167-0115(90)90115-D] [PMID: 2176308] 
[116] 
Sagan, S.; Chassaing, G.; Pradier, L.; Lavielle, S. Tachykinin peptides affect differently the second messenger pathways after binding to CHO-expressed human NK-1 receptors. J. Pharmacol. Exp. Ther.,  1996, 276(3), 1039-1048.
[PMID: 8786533] 
[117] 
Burman, A.C.; Prasad, S.; Mukherhee, R.; Jaggi, M.; Singh, A.T. Substance P analogs for the treatment of cancer., 2002.
[118] 
Prasad, S.; Mathur, A.; Jaggi, M.; Singh, A.T.; Mukherjee, R. Substance P analogs containing alpha,alpha-dialkylated amino acids with potent anticancer activity. J. Pept. Sci.,  2007, 13(8), 544-548.
[http://dx.doi.org/10.1002/psc.886] [PMID: 17617800] 
[119] 
Cavelier, F.; Marchand, D.; Martinez, J.; Sagan, S. Biological activity of silylated amino acid containing substance P analogues. J. Pept. Res.,  2004, 63(3), 290-296.
[http://dx.doi.org/10.1111/j.1399-3011.2004.00145.x] [PMID: 15049841] 
[120] 
Pradier, L.; Ménager, J.; Le Guern, J.; Bock, M.D.; Heuillet, E.; Fardin, V.; Garret, C.; Doble, A.; Mayaux, J.F. Septide: an agonist for the NK1 receptor acting at a site distinct from substance P. Mol. Pharmacol.,  1994, 45(2), 287-293.
[PMID: 7509440] 
[121] 
Nachman, R.J.; Mahdian, K.; Nässel, D.R.; Isaac, R.E.; Pryor, N.; Smagghe, G. Biostable multi-Aib analogs of tachykinin-related peptides demonstrate potent oral aphicidal activity in the pea aphid Acyrthosiphon pisum (Hemiptera: Aphidae). Peptides,  2011, 32(3), 587-594.
[http://dx.doi.org/10.1016/j.peptides.2010.09.013] [PMID: 20869418] 
[122] 
Ward, P.; Ewan, G.B.; Jordan, C.C.; Ireland, S.J.; Hagan, R.M.; Brown, J.R. Potent and highly selective neurokinin antagonists. J. Med. Chem.,  1990, 33(7), 1848-1851.
[http://dx.doi.org/10.1021/jm00169a003] [PMID: 1694545] 
[123] 
Cascieri, M.A.; Chicchi, G.G.; Freidinger, R.M.; Colton, C.D.; Perlow, D.S.; Williams, B.; Curtis, N.R.; McKnight, A.T.; Maguire, J.J.; Veber, D.F.; Liang, T. Conformationally constrained tachykinin analogs which are selective ligands for the eledoisin binding site. Mol. Pharmacol.,  1986, 29(1), 34-38.
[PMID: 2418347] 
[124] 
Guo, J.Z.; Yoshioka, K.; Yanagisawa, M.; Hosoki, R.; Hagan, R.M.; Otsuka, M. Depression of primary afferent-evoked responses by GR71251 in the isolated spinal cord of the neonatal rat. Br. J. Pharmacol.,  1993, 110(3), 1142-1148.
[http://dx.doi.org/10.1111/j.1476-5381.1993.tb13933.x] [PMID: 7507777] 
[125] 
Guo, J.Z.; Yoshioka, K.; Zhao, F.Y.; Hosoki, R.; Maehara, T.; Yanagisawa, M.; Hagan, R.M.; Otsuka, M. Pharmacological characterization of GR82334, a tachykinin NK1 receptor antagonist, in the isolated spinal cord of the neonatal rat. Eur. J. Pharmacol.,  1995, 281(1), 49-54.
[http://dx.doi.org/10.1016/0014-2999(95)00228-D] [PMID: 8566116] 
[126] 
Malikayil, J.A.; Harbeson, S.L. Conformation of a neurokinin antagonist in solution. 2D NMR and restrained molecular dynamics study. Int. J. Pept. Protein Res.,  1992, 39(6), 497-505.
[http://dx.doi.org/10.1111/j.1399-3011.1992.tb00280.x] [PMID: 1328098] 
[127] 
Hanessian, S.; Ronan, B.; Laoui, A. Design and synthesis of a prototype model antagonist of tachykinin NK-2 receptor. Bioorg. Med. Chem. Lett.,  1994, 4(11), 1397-1400.
[http://dx.doi.org/10.1016/S0960-894X(01)80369-3] 
[128] 
Asche, G.; Kunz, H.; Nar, H.; Köppen, H.; Briem, H.; Pook, K.H.; Schiller, P.W.; Chung, N.N.; Lemieux, C.; Esser, F. Synthesis of cyclic dipeptide templates, their incorporation into peptides and studies on their conformational and biological properties. J. Pept. Res.,  1998, 51(5), 323-336.
[http://dx.doi.org/10.1111/j.1399-3011.1998.tb01223.x] [PMID: 9606012] 
[129] 
Smith, M.E.; Adkins, H. The relative reactivity of amines in the aminolysis of amides1. J. Am. Chem. Soc.,  1938, 60(3), 657-663.
[http://dx.doi.org/10.1021/ja01270a048] 
[130] 
Smith, P.W.; McElroy, A.B.; Pritchard, J.M.; Deal, M.J.; Ewan, G.B.; Hagan, R.M.; Ireland, S.J.; Ball, D.; Beresford, I.; Sheldrick, R.; Jordan, C.C.; Ward, P. Low-molecular-weight neurokinin-NK(2) antagonists. Bioorg. Med. Chem. Lett.,  1993, 3(5), 931-936.
[http://dx.doi.org/10.1016/S0960-894X(00)80695-2] 
[131] 
Stables, J.M.; Beresford, I.J.M.; Arkinstall, S.; Ireland, S.J.; Walsh, D.M.; Seale, P.W.; Ward, P.; Hagan, R.M. GR138676, a novel peptidic tachykinin antagonist which is potent at NK3 receptors. Neuropeptides,  1994, 27(6), 333-341.
[http://dx.doi.org/10.1016/0143-4179(94)90059-0] [PMID: 7534879] 
[132] 
Yudin, A.K. Macrocycles: lessons from the distant past, recent developments, and future directions. Chem. Sci. (Camb.),  2015, 6(1), 30-49.
[http://dx.doi.org/10.1039/C4SC03089C] [PMID: 28553456] 
[133] 
McKnight, A.T.; Maguire, J.J.; Elliott, N.J.; Fletcher, A.E.; Foster, A.C.; Tridgett, R.; Williams, B.J.; Longmore, J.; Iversen, L.L. Pharmacological specificity of novel, synthetic, cyclic peptides as antagonists at tachykinin receptors. Br. J. Pharmacol.,  1991, 104(2), 355-360.
[http://dx.doi.org/10.1111/j.1476-5381.1991.tb12435.x] [PMID: 1665732] 
[134] 
Williams, B.J.; Curtis, N.R.; McKnight, A.T.; Maguire, J.J.; Young, S.C.; Veber, D.F.; Baker, R. Cyclic peptides as selective tachykinin antagonists. J. Med. Chem.,  1993, 36(1), 2-10.
[http://dx.doi.org/10.1021/jm00053a001] [PMID: 7678430] 
[135] 
Hagiwara, D.; Miyake, H.; Igari, N.; Morimoto, H.; Murai, M.; Fujii, T.; Matsuo, M. Design of a novel dipeptide substance-P antagonist FK888. Regul. Pept.,  1993, 46(1-2), 332-334.
[http://dx.doi.org/10.1016/0167-0115(92)90921-G] [PMID: 7692528] 
[136] 
Egleton, R.D.; Mitchell, S.A.; Huber, J.D.; Janders, J.; Stropova, D.; Polt, R.; Yamamura, H.I.; Hruby, V.J.; Davis, T.P. Improved bioavailability to the brain of glycosylated Met-enkephalin analogs. Brain Res.,  2000, 881(1), 37-46.
[http://dx.doi.org/10.1016/S0006-8993(00)02794-3] [PMID: 11033091] 
[137] 
Polt, R.; Porreca, F.; Szabò, L.Z.; Bilsky, E.J.; Davis, P.; Abbruscato, T.J.; Davis, T.P.; Harvath, R.; Yamamura, H.I.; Hruby, V.J. Glycopeptide enkephalin analogues produce analgesia in mice: evidence for penetration of the blood-brain barrier. Proc. Natl. Acad. Sci. USA,  1994, 91(15), 7114-7118.
[http://dx.doi.org/10.1073/pnas.91.15.7114] [PMID: 8041755] 
[138] 
Pinzani, D.; Papini, A.M.; Vallecchi, M.E.; Chelli, M.; Ginanneschi, M.; Rapi, G.; Quartara, L.; Patacchini, R.; Maggi, C.A.; Arcamone, F.M. Glycosyl derivatives of NK2 tachykinin receptor antagonists. Bioorg. Med. Chem. Lett.,  1996, 6(4), 367-372.
[http://dx.doi.org/10.1016/0960-894X(96)00039-X] 
[139] 
Hirayama, Y.; Lei, Y.H.; Barnes, P.J.; Rogers, D.F. Effects of two novel tachykinin antagonists, FK224 and FK888, on neurogenic airway plasma exudation, bronchoconstriction and systemic hypotension in guinea-pigs in vivo. Br. J. Pharmacol.,  1993, 108(3), 844-851.
[http://dx.doi.org/10.1111/j.1476-5381.1993.tb12888.x] [PMID: 7682142] 
[140] 
Moureau, F.; Neuwels, M.; Dogimont, C.; Goldstein, S.; Massingham, R. Conformational analysis of pseudo-peptides: The case of FK888, a potent and selective substance P receptor antagonist. Lett. Pept. Sci.,  1998, 5(2-3), 155-158.
[http://dx.doi.org/10.1007/BF02443460] 
[141] 
Hagiwara, D.; Miyake, H.; Morimoto, H.; Murai, M.; Fujii, T.; Matsuo, M. Studies on neurokinin antagonists. 1. The design of novel tripeptides possessing the glutaminyl-D-tryptophylphenylalanine sequence as substance P antagonists. J. Med. Chem.,  1992, 35(11), 2015-2025.
[http://dx.doi.org/10.1021/jm00089a011] [PMID: 1375965] 
[142] 
Hagiwara, D.; Miyake, H.; Morimoto, H.; Murai, M.; Fujii, T.; Matsuo, M. Studies on neurokinin antagonists. 2. Design and structure-activity relationships of novel tripeptide substance P antagonists, N alpha-[N alpha-(N alpha-acetyl-L-threonyl)-N1-formyl-D-tryptophyl]-N- methyl-N-(phenylmethyl)-L-phenylalaninamide and its related compounds. J. Med. Chem.,  1992, 35(17), 3184-3191.
[http://dx.doi.org/10.1021/jm00095a013] [PMID: 1380560] 
[143] 
Morimoto, H.; Murai, M.; Maeda, Y.; Hagiwara, D.; Miyake, H.; Matsuo, M.; Fujii, T. FR 113680: a novel tripeptide substance P antagonist with NK1 receptor selectivity. Br. J. Pharmacol.,  1992, 106(1), 123-126.
[http://dx.doi.org/10.1111/j.1476-5381.1992.tb14303.x] [PMID: 1380378] 
[144] 
Caliendo, G.; Calignano, A.; Grieco, P.; Mancuso, F.; Perissutti, E.; Santini, A.; Santagada, V. Synthesis and biological activity of tripeptide FR113680 analogues containing unconventional amino acids. Biopolymers,  1995, 36(4), 409-414.
[http://dx.doi.org/10.1002/bip.360360404] [PMID: 7578938] 
[145] 
Fujii, T.; Murai, M.; Morimoto, H.; Maeda, Y.; Yamaoka, M.; Hagiwara, D.; Miyake, H.; Ikari, N.; Matsuo, M. Pharmacological profile of a high affinity dipeptide NK1 receptor antagonist, FK888. Br. J. Pharmacol.,  1992, 107(3), 785-789.
[http://dx.doi.org/10.1111/j.1476-5381.1992.tb14524.x] [PMID: 1282073] 
[146] 
Sisto, A.; Bonelli, F.; Centini, F.; Fincham, C.I.; Potier, E.; Monteagudo, E.; Lombardi, P.; Arcamone, F.; Goso, C.; Manzini, S.; Giolitti, A.; Maggi, C.A.; Venanzi, M.; Pispisa, B. Synthesis and biological evaluation of novel NK-1 tachykinin receptor antagonists: the use of cycloalkyl amino acids as a template. Biopolymers,  1995, 36(4), 511-524.
[http://dx.doi.org/10.1002/bip.360360413] [PMID: 7578945] 
[147] 
MacLeod, A.M.; Merchant, K.J.; Brookfield, F.; Kelleher, F.; Stevenson, G.; Owens, A.P.; Swain, C.J.; Casiceri, M.A.; Sadowski, S.; Ber, E.; Ber, E.; Strader, C.D.; Macintyre, D.E.; Metzger, J.M.; Ball, R.G. Identification of L-tryptophan derivatives with potent and selective antagonist activity at the NK1 receptor. J. Med. Chem.,  1994, 37(9), 1269-1274.
[http://dx.doi.org/10.1021/jm00035a006] [PMID: 7513763] 
[148] 
Cirillo, R.; Astolfi, M.; Conte, B.; Lopez, G.; Parlani, M.; Terracciano, R.; Fincham, C.I.; Manzini, S. Pharmacology of the peptidomimetic, MEN 11149, a new potent, selective and orally effective tachykinin NK1 receptor antagonist. Eur. J. Pharmacol.,  1998, 341(2-3), 201-209.
[http://dx.doi.org/10.1016/S0014-2999(97)01453-2] [PMID: 9543241] 
[149] 
Cirillo, R.; Astolfi, M.; Conte, B.; Lopez, G.; Parlani, M.; Sacco, G.; Terracciano, R.; Fincham, C.I.; Sisto, A.; Evangelista, S.; Maggi, C.A.; Manzini, S. Pharmacology of MEN 11467: a potent new selective and orally- effective peptidomimetic tachykinin NK(1) receptor antagonist. Neuropeptides,  2001, 35(3-4), 137-147.
[http://dx.doi.org/10.1054/npep.2001.0855] [PMID: 11884203] 
[150] 
Astolfi, M.; Patacchini, R.; Maggi, M.; Manzini, S. Improved discriminatory properties between human and murine tachykinin NK1 receptors of MEN 10930: a new potent and competitive antagonist. Neuropeptides,  1997, 31(4), 373-379.
[http://dx.doi.org/10.1016/S0143-4179(97)90074-3] [PMID: 9308026] 
[151] 
Walpole, C.; Ko, S.Y.; Brown, M.; Beattie, D.; Campbell, E.; Dickenson, F.; Ewan, S.; Hughes, G.A.; Lemaire, M.; Lerpiniere, J.; Patel, S.; Urban, L. 2-Nitrophenylcarbamoyl-(S)-prolyl-(S)-3-(2-naphthyl)alanyl-N-benzyl-N - methylamide (SDZ NKT 343), a potent human NK1 tachykinin receptor antagonist with good oral analgesic activity in chronic pain models. J. Med. Chem.,  1998, 41(17), 3159-3173.
[http://dx.doi.org/10.1021/jm970499g] [PMID: 9703462] 
[152] 
Herr, R.J. 5-Substituted-1H-tetrazoles as carboxylic acid isosteres: medicinal chemistry and synthetic methods. Bioorg. Med. Chem.,  2002, 10(11), 3379-3393.
[http://dx.doi.org/10.1016/S0968-0896(02)00239-0] [PMID: 12213451] 
[153] 
Bonnet, J.; Kucharczyk, N.; Robineau, P.; Lonchampt, M.; Dacquet, C.; Regoli, D.; Fauchère, J.L.; Canet, E. A water-soluble, stable dipeptide NK1 receptor-selective neurokinin receptor antagonist with potent in vivo pharmacological effects: S18523. Eur. J. Pharmacol.,  1996, 310(1), 37-46.
[http://dx.doi.org/10.1016/0014-2999(96)00362-7] [PMID: 8880065] 
[154] 
Fauchere, J.L.; Kucharczyk, N.; Jacoby, E.; Lonchampt, M.; Robineau, P.; Dacquet, C.; Regoli, D.; Canet, E. The dipeptide neurokinin-1 receptor antagonist S19752 is a potent and long-acting inhibitor of bronchoconstriction when administered by aerosol to the guinea pig. Bioorg. Med. Chem. Lett.,  1997, 7(2), 203-208.
[http://dx.doi.org/10.1016/S0960-894X(96)00604-X] 
[155] 
Jacoby, E.; Boudon, A.; Kucharczyk, N.; Michel, A.; Fauchère, J.L. A structural rationale for the design of water soluble peptide-derived neurokinin-1 antagonists. J. Recept. Signal Transduct. Res.,  1997, 17(6), 855-873.
[http://dx.doi.org/10.3109/10799899709039160] [PMID: 9365934] 
[156] 
Millet, R.; Domarkas, J.; Rigo, B.; Goossens, L.; Goossens, J.F.; Houssin, R.; Hénichart, J.P. Novel potent substance P and neurokinin A receptor antagonists. Conception, synthesis and biological evaluation of indolizine derivatives. Bioorg. Med. Chem.,  2002, 10(9), 2905-2912.
[http://dx.doi.org/10.1016/S0968-0896(02)00144-X] [PMID: 12110311] 
[157] 
Millet, R.; Goossens, J.F.; Bertrand-Caumont, K.; Chavatte, P.; Houssin, R.; Henichart, J.P. Synthesis and biological evaluation of conformationally restricted derivatives of tryptophan as NK1/NK2 ligands. Lett. Pept. Sci.,  1999, 6(4), 221-233.
[http://dx.doi.org/10.1007/BF02443509] 
[158] 
Millet, R.; Goossens, J.F.; Bertrand-Caumont, K.; Houssin, R.; Henichart, J.P. Synthesis and biological evaluation of tripeptide derivatives of Cbz-Gly-Leu-Trp-OBzl(CF3)(2) as NK1/NK2 ligands. Lett. Pept. Sci.,  1999, 6(4), 255-262.
[http://dx.doi.org/10.1007/BF02443514] 
[159] 
Millet, R.; Goossens, L.; Bertrand-Caumont, K.; Goossens, J.F.; Houssin, R.; Hénichart, J.P. A flexible approach to the design of new potent substance P receptor ligands. J. Pharm. Pharmacol.,  2001, 53(7), 929-934.
[http://dx.doi.org/10.1211/0022357011776324] [PMID: 11480541] 
[160] 
Millet, R.; Goossens, L.; Bertrand-Caumont, K.; Houssin, R.; Rigo, B.; Goossens, J.F.; Henichart, J.P. New substance P receptor antagonists. Conception, synthesis and biological evaluation of spirolactam derivatives and their tripeptide Cbz-Pro-Leu-Trp-OBzl(CF3)(2) and lactam pseudopeptide derivatives. Lett. Pept. Sci.,  2000, 7(5), 269-279.
[http://dx.doi.org/10.1023/A:1011867801367] 
[161] 
Sisto, A.; Caciagli, V.; Altamura, M.; Giolitti, A.; Fedi, V.; Guidi, A.; Giannotti, D.; Harmat, N.; Nannicini, R.; Pasqui, F.; Maggi, C.A. Linear basic compounds having NK-2 antagonist
 activity and formulations thereof. WO2003037916A2. 2003.
[162] 
Meini, S.; Bellucci, F.; Catalani, C.; Cucchi, P.; Patacchini, R.; Rotondaro, L.; Altamura, M.; Giuliani, S.; Giolitti, A.; Maggi, C.A. Mutagenesis at the human tachykinin NK(2) receptor to define the binding site of a novel class of antagonists. Eur. J. Pharmacol.,  2004, 488(1-3), 61-69.
[http://dx.doi.org/10.1016/j.ejphar.2004.02.016] [PMID: 15044036] 
[163] 
Fedi, V.; Altamura, M.; Catalioto, R.M.; Giannotti, D.; Giolitti, A.; Giuliani, S.; Guidi, A.; Harmat, N.J.S.; Lecci, A.; Meini, S.; Nannicini, R.; Pasqui, F.; Tramontana, M.; Triolo, A.; Maggi, C.A. Discovery of a new series of potent and selective linear tachykinin NK2 receptor antagonists. J. Med. Chem.,  2007, 50(20), 4793-4807.
[http://dx.doi.org/10.1021/jm070289w] [PMID: 17850056] 
[164] 
Veber, D.F.; Johnson, S.R.; Cheng, H.Y.; Smith, B.R.; Ward, K.W.; Kopple, K.D. Molecular properties that influence the oral bioavailability of drug candidates. J. Med. Chem.,  2002, 45(12), 2615-2623.
[http://dx.doi.org/10.1021/jm020017n] [PMID: 12036371] 
[165] 
Cialdai, C.; Tramontana, M.; Patacchini, R.; Lecci, A.; Catalani, C.; Catalioto, R.M.; Meini, S.; Valenti, C.; Altamura, M.; Giuliani, S.; Maggi, C.A. MEN15596, a novel nonpeptide tachykinin NK2 receptor antagonist. Eur. J. Pharmacol.,  2006, 549(1-3), 140-148.
[http://dx.doi.org/10.1016/j.ejphar.2006.08.021] [PMID: 16979621] 
[166] 
Meini, S.; Bellucci, F.; Catalani, C.; Cucchi, P.; Giolitti, A.; Santicioli, P.; Giuliani, S. Multifaceted approach to determine the antagonist molecular mechanism and interaction of ibodutant ([1-(2-phenyl-1R-[[1-(tetrahydropyran-4-ylmethyl)-piperidin-4-ylmethyl]-carbamoyl]-ethylcarbamoyl)-cyclopentyl]-amide) at the human tachykinin NK2 receptor. J. Pharmacol. Exp. Ther.,  2009, 329(2), 486-495.
[http://dx.doi.org/10.1124/jpet.108.150201] [PMID: 19218528] 
[167] 
Santicioli, P.; Meini, S.; Giuliani, S.; Lecci, A.; Maggi, C.A. Antagonist profile of ibodutant at the tachykinin NK(2) receptor in guinea pig isolated bronchi. Eur. J. Pharmacol.,  2013, 720(1-3), 180-185.
[http://dx.doi.org/10.1016/j.ejphar.2013.10.029] [PMID: 24436990] 
[168] 
Santicioli, P.; Meini, S.; Giuliani, S.; Catalani, C.; Bechi, P.; Riccadonna, S.; Ringressi, M.N.; Maggi, C.A. Characterization of ibodutant at NK(2) receptor in human colon. Eur. J. Pharmacol.,  2013, 702(1-3), 32-37.
[http://dx.doi.org/10.1016/j.ejphar.2013.01.021] [PMID: 23376417] 
[169] 
Zaman, S.; Woods, A.J.; Watson, J.W.; Reynolds, D.J.M.; Andrews, P.L.R. The effect of the NK1 receptor antagonist CP-99,994 on emesis and c-fos protein induction by loperamide in the ferret. Neuropharmacology,  2000, 39(2), 316-323.
[http://dx.doi.org/10.1016/S0028-3908(99)00113-6] [PMID: 10670427] 
[170] 
Gensini, M.; Altamura, M.; Dimoulas, T.; Fedi, V.; Giannotti, D.; Giuliani, S.; Guidi, A.; Harmat, N.J.S.; Meini, S.; Nannicini, R.; Pasqui, F.; Tramontana, M.; Triolo, A.; Maggi, C.A. Modulation on C- and N-terminal moieties of a series of potent and selective linear tachykinin NK(2) receptor antagonists. ChemMedChem,  2010, 5(1), 65-78.
[http://dx.doi.org/10.1002/cmdc.200900389] [PMID: 19957262] 
[171] 
Harbeson, S.; Buck, S. Cyclic neurokinin antagonists. EP 0412542 B1. 1996.
[172] 
Maggi, C.A.; Quartara, L.; Patacchini, R.; Giuliani, S.; Barbanti, G.; Turini, D.; Giachetti, A. MEN 10,573 and MEN 10,612, novel cyclic pseudopeptides which are potent tachykinin NK-2 receptor antagonists. Regul. Pept.,  1993, 47(2), 151-158.
[http://dx.doi.org/10.1016/0167-0115(93)90419-9] [PMID: 8234901] 
[173] 
Ha, J.M.; Shin, S.Y.; Hong, H.N.; Suh, D.J.; Jang, T.S.; Kang, S.W.; Kuean, S.J.; Ha, B.J. Structure-antagonistic activity relationships of an NK-2 tachykinin receptor antagonist, L-659,877 and its analogues. J. Biochem. Mol. Biol.,  1996, 29(5), 429-435.
[174] 
Quartara, L.; Fabbri, G.; Ricci, R.; Patacchini, R.; Pestellini, V.; Maggi, C.A.; Pavone, V.; Giachetti, A.; Arcamone, F. Influence of lipophilicity on the biological activity of cyclic pseudopeptide NK-2 receptor antagonists. J. Med. Chem.,  1994, 37(21), 3630-3638.
[http://dx.doi.org/10.1021/jm00047a020] [PMID: 7932590] 
[175] 
Patacchini, R.; Giuliani, S.; Lazzeri, M.; Turini, A.; Quartara, L.; Maggi, C.A. Effect of several bicyclic peptide and cyclic pseudopeptide tachykinin NK2 receptor antagonists in the human isolated ileum and colon. Neuropeptides,  1997, 31(1), 71-77.
[http://dx.doi.org/10.1016/S0143-4179(97)90023-8] [PMID: 9574841] 
[176] 
Giuliani, S.; Patacchini, R.; Lazzeri, M.; Benaim, G.; Turini, D.; Quartara, L.; Maggi, C.A. Effect of several bicyclic peptide and cyclic pseudopeptide tachykinin NK2 receptor antagonists in the human isolated urinary bladder. J. Auton. Pharmacol.,  1996, 16(5), 251-259.
[http://dx.doi.org/10.1111/j.1474-8673.1996.tb00359.x] [PMID: 9023669] 
[177] 
Hölzemann, G.; Löw, A.; Harting, J.; Greiner, H.E. Cyclic hexapeptide NK-2 antagonists. Int. J. Pept. Protein Res.,  1994, 44(2), 105-111.
[http://dx.doi.org/10.1111/j.1399-3011.1994.tb00564.x] [PMID: 7527014] 
[178] 
Wollborn, U.; Brunne, R.M.; Harting, J.; Hölzemann, G.; Leibfritz, D. Comparative conformational analysis and in vitro pharmacological evaluation of three cyclic hexapeptide NK-2 antagonists. Int. J. Pept. Protein Res.,  1993, 41(4), 376-384.
[http://dx.doi.org/10.1111/j.1399-3011.1993.tb00453.x] [PMID: 8388367] 
[179] 
Pavone, V.; Lombardi, A.; Pedone, C.; Maggi, C.A.; Quartara, L. Tachykinin antagonist tricyclic compounds, preparation of same and pharmaceutical compositions containing such compounds., 1993.
[180] 
Maggi, C.A.; Astolfi, M.; Giuliani, S.; Goso, C.; Manzini, S.; Meini, S.; Patacchini, R.; Pavone, V.; Pedone, C.; Quartara, L.; Renzetti, A.R.; Giachetti, A. MEN 10,627, a novel polycyclic peptide antagonist of tachykinin NK2 receptors. J. Pharmacol. Exp. Ther.,  1994, 271(3), 1489-1500.
[PMID: 7996462] 
[181] 
Santicioli, P.; Giuliani, S.; Patacchini, R.; Tramontana, M.; Criscuoli, M.; Maggi, C.A. MEN 11420, a potent and selective tachykinin NK2 receptor antagonist in the guinea-pig and human colon. Naunyn Schmiedebergs Arch. Pharmacol.,  1997, 356(5), 678-688.
[http://dx.doi.org/10.1007/PL00005105] [PMID: 9402049] 
[182] 
Lippi, A.; Criscuoli, M.; Guelfi, M.; Santicioli, P.; Maggi, C.A. Pharmacokinetics of the bicyclic peptide tachykinin NK2 receptor antagonist MEN 11420 (nepadutant) in rats. Drug Metab. Dispos.,  1998, 26(11), 1077-1081.
[PMID: 9806949] 
[183] 
Catalioto, R.M.; Criscuoli, M.; Cucchi, P.; Giachetti, A.; Gianotti, D.; Giuliani, S.; Lecci, A.; Lippi, A.; Patacchini, R.; Quartara, L.; Renzetti, A.R.; Tramontana, M.; Arcamone, F.; Maggi, C.A. MEN 11420 (Nepadutant), a novel glycosylated bicyclic peptide tachykinin NK2 receptor antagonist. Br. J. Pharmacol.,  1998, 123(1), 81-91.
[http://dx.doi.org/10.1038/sj.bjp.0701587] [PMID: 9484857] 
[184] 
Lördal, M.; Navalesi, G.; Theodorsson, E.; Maggi, C.A.; Hellström, P.M. A novel tachykinin NK2 receptor antagonist prevents motility-stimulating effects of neurokinin A in small intestine. Br. J. Pharmacol.,  2001, 134(1), 215-223.
[http://dx.doi.org/10.1038/sj.bjp.0704217] [PMID: 11522614] 
[185] 
Giannotti, D.; Perrotta, E.; Di Bugno, C.; Nannicini, R.; Harmat, N.J.S.; Giolitti, A.; Patacchini, R.; Renzetti, A.R.; Rotondaro, L.; Giuliani, S.; Altamura, M.; Maggi, C.A. Discovery of potent cyclic pseudopeptide human tachykinin NK-2 receptor antagonists. J. Med. Chem.,  2000, 43(22), 4041-4044.
[http://dx.doi.org/10.1021/jm0010217] [PMID: 11063600] 
[186] 
Altamura, M.; Criscuoli, M.; Guidi, A.; Perrotta, E.; Maggi, C.A. Monocyclic compounds having NK-2 antagonist action and compositions containing them. WO 20008046 A1. 2000.
[187] 
Harmat, N.J.S.; Giannotti, D.; Nannicini, R.; Perrotta, E.; Criscuoli, M.; Patacchini, R.; Renzetti, A.R.; Giuliani, S.; Altamura, M.; Maggi, C.A. Insertion of 2-carboxysuccinate and tricarballylic acid fragments into cyclic-pseudopeptides: new antagonists for the human tachykinin NK-2 receptor. Bioorg. Med. Chem. Lett.,  2002, 12(4), 693-696.
[http://dx.doi.org/10.1016/S0960-894X(01)00841-1] [PMID: 11844703] 
[188] 
Fedi, V.; Altamura, M.; Balacco, G.; Canfarini, F.; Criscuoli, M.; Giannotti, D.; Giolitti, A.; Giuliani, S.; Guidi, A.; Harmat, N.J.S.; Nannicini, R.; Pasqui, F.; Patacchini, R.; Perrotta, E.; Tramontana, M.; Triolo, A.; Maggi, C.A. Insertion of an aspartic acid moiety into cyclic pseudopeptides: synthesis and biological characterization of potent antagonists for the human Tachykinin NK-2 receptor. J. Med. Chem.,  2004, 47(27), 6935-6947.
[http://dx.doi.org/10.1021/jm040832y] [PMID: 15615542] 
[189] 
Seguin, L.; Le Marouille-Girardon, S.; Millan, M.J. Antinociceptive profiles of non-peptidergic neurokinin1 and neurokinin2 receptor antagonists: a comparison to other classes of antinociceptive agent. Pain,  1995, 61(2), 325-343.
[http://dx.doi.org/10.1016/0304-3959(94)00194-J] [PMID: 7659444] 
[190] 
Campbell, E.A.; Gentry, C.T.; Patel, S.; Panesar, M.S.; Walpole, C.S.J.; Urban, L. Selective neurokinin-1 receptor antagonists are anti-hyperalgesic in a model of neuropathic pain in the guinea-pig. Neuroscience,  1998, 87(3), 527-532.
[http://dx.doi.org/10.1016/S0306-4522(98)00318-2] [PMID: 9758219] 
[191] 
Sakurada, T.; Sakurada, C.; Tan-No, K.; Kisara, K. Neurokinin receptor antagonists - Therapeutic potential in the treatment of pain syndromes. CNS Drugs,  1997, 8(6), 436-447.
[http://dx.doi.org/10.2165/00023210-199708060-00002] 
[192] 
Dionne, R.A.; Max, M.B.; Gordon, S.M.; Parada, S.; Sang, C.; Gracely, R.H.; Sethna, N.F.; MacLean, D.B. The substance P receptor antagonist CP-99,994 reduces acute postoperative pain. Clin. Pharmacol. Ther.,  1998, 64(5), 562-568.
[http://dx.doi.org/10.1016/S0009-9236(98)90140-0] [PMID: 9834049] 
[193] 
Albany, C.; Brames, M.J.; Fausel, C.; Johnson, C.S.; Picus, J.; Einhorn, L.H. Randomized, double-blind, placebo-controlled, phase III cross-over study evaluating the oral neurokinin-1 antagonist aprepitant in combination with a 5HT3 receptor antagonist and dexamethasone in patients with germ cell tumors receiving 5-day cisplatin combination chemotherapy regimens: a hoosier oncology group study. J. Clin. Oncol.,  2012, 30(32), 3998-4003.
[http://dx.doi.org/10.1200/JCO.2011.39.5558] [PMID: 22915652] 
[194] 
Ang, D.; Pauwels, A.; Akyuz, F.; Vos, R.; Tack, J. Influence of a neurokinin-1 receptor antagonist (aprepitant) on gastric sensorimotor function in healthy volunteers. Neurogastroenterol. Motil.,  2013, 25(12), e830-e838.
[http://dx.doi.org/10.1111/nmo.12210] [PMID: 23991829] 
[195] 
Barrett, J.S.; Spitsin, S.; Moorthy, G.; Barrett, K.; Baker, K.; Lackner, A.; Tulic, F.; Winters, A.; Evans, D.L.; Douglas, S.D. Pharmacologic rationale for the NK1R antagonist, aprepitant as adjunctive therapy in HIV. J. Transl. Med.,  2016, 14(1), 148.
[http://dx.doi.org/10.1186/s12967-016-0904-y] [PMID: 27230663] 
[196] 
Bayati, S.; Bashash, D.; Ahmadian, S.; Safaroghli-Azar, A.; Alimoghaddam, K.; Ghavamzadeh, A.; Ghaffari, S.H. Inhibition of tachykinin NK1 receptor using aprepitant induces apoptotic cell death and G1 arrest through Akt/p53 axis in pre-B acute lymphoblastic leukemia cells. Eur. J. Pharmacol.,  2016, 791, 274-283.
[http://dx.doi.org/10.1016/j.ejphar.2016.09.006] [PMID: 27609608] 
[197] 
Cristofori, F.; Thapar, N.; Saliakellis, E.; Kumaraguru, N.; Elawad, M.; Kiparissi, F.; Köglmeier, J.; Andrews, P.; Lindley, K.J.; Borrelli, O. Efficacy of the neurokinin-1 receptor antagonist aprepitant in children with cyclical vomiting syndrome. Aliment. Pharmacol. Ther.,  2014, 40(3), 309-317.
[http://dx.doi.org/10.1111/apt.12822] [PMID: 24898244] 
[198] 
He, A.; Alhariri, J.M.; Sweren, R.J.; Kwatra, M.M.; Kwatra, S.G. Aprepitant for the treatment of chronic refractory pruritus. BioMed Res. Int.,  2017, 20174790810
[http://dx.doi.org/10.1155/2017/4790810] [PMID: 29057261] 
[199] 
Jones, J.D.; Speer, T.; Comer, S.D.; Ross, S.; Rotrosen, J.; Reid, M.S. Opioid-like effects of the neurokinin 1 antagonist aprepitant in patients maintained on and briefly withdrawn from methadone. Am. J. Drug Alcohol Abuse,  2013, 39(2), 86-91.
[http://dx.doi.org/10.3109/00952990.2012.762372] [PMID: 23421568] 
[200] 
Ladizinski, B.; Bazakas, A.; Olsen, E.A. Aprepitant: a novel neurokinin-1 receptor/substance P antagonist as antipruritic therapy in cutaneous T-cell lymphoma. J. Am. Acad. Dermatol.,  2012, 67(5), e198-e199.
[http://dx.doi.org/10.1016/j.jaad.2012.02.008] [PMID: 23062910] 
[201] 
Mannangatti, P.; Sundaramurthy, S.; Ramamoorthy, S.; Jayanthi, L.D. Differential effects of aprepitant, a clinically used neurokinin-1 receptor antagonist on the expression of conditioned psychostimulant versus opioid reward. Psychopharmacology (Berl.),  2017, 234(4), 695-705.
[http://dx.doi.org/10.1007/s00213-016-4504-6] [PMID: 28013351] 
[202] 
Mao, S.M.; Li, C.D.; Sun, H.W. Aprepitant, a NK1 receptor antagonist, improves both airway inflammation and depressive-like behaviors in a rat model with asthma and depression. Int. J. Clin. Exp. Med.,  2016, 9(6), 9504-9512.
[203] 
Ständer, S.; Siepmann, D.; Herrgott, I.; Sunderkötter, C.; Luger, T.A. Targeting the neurokinin receptor 1 with aprepitant: a novel antipruritic strategy. PLoS One,  2010, 5(6)e10968
[http://dx.doi.org/10.1371/journal.pone.0010968] [PMID: 20532044] 
[204] 
Walsh, S.L.; Heilig, M.; Nuzzo, P.A.; Henderson, P.; Lofwall, M.R. Effects of the NK1 antagonist, aprepitant, on response to oral and intranasal oxycodone in prescription opioid abusers. Addict. Biol.,  2013, 18(2), 332-343.
[http://dx.doi.org/10.1111/j.1369-1600.2011.00419.x] [PMID: 22260216] 
[205] 
King, T.; Gardell, L.R.; Wang, R.; Vardanyan, A.; Ossipov, M.H.; Malan, T.P., Jr; Vanderah, T.W.; Hunt, S.P.; Hruby, V.J.; Lai, J.; Porreca, F. Role of NK-1 neurotransmission in opioid-induced hyperalgesia. Pain,  2005, 116(3), 276-288.
[http://dx.doi.org/10.1016/j.pain.2005.04.014] [PMID: 15964684] 
[206] 
Misterek, K.; Maszczynska, I.; Dorociak, A.; Gumulka, S.W.; Carr, D.B.; Szyfelbein, S.K.; Lipkowski, A.W. Spinal co-administration of peptide substance P antagonist increases antinociceptive effect of the opioid peptide biphalin. Life Sci.,  1994, 54(14), 939-944.
[http://dx.doi.org/10.1016/0024-3205(94)00494-3] [PMID: 7511201] 
[207] 
Giri, A.K.; Hruby, V.J. Investigational peptide and peptidomimetic μ and δ opioid receptor agonists in the relief of pain. Expert Opin. Investig. Drugs,  2014, 23(2), 227-241.
[http://dx.doi.org/10.1517/13543784.2014.856879] [PMID: 24329035] 
[208] 
Lipkowski, A.W.; Misicka, A.; Carr, D.B.; Ronsisvalle, G.; Kosson, D.; Bonney, L.M. Neuropeptide mimetics for pain management. Pure Appl. Chem.,  2004, 76(5), 941-950.
[http://dx.doi.org/10.1351/pac200476050941] 
[209] 
Kleczkowska, P.; Lipkowski, A.W.; Tourwé, D.; Ballet, S. Hybrid opioid/non-opioid ligands in pain research. Curr. Pharm. Des.,  2013, 19(42), 7435-7450.
[http://dx.doi.org/10.2174/138161281942140105165646] [PMID: 23448481] 
[210] 
Bonney, I.M.; Foran, S.E.; Marchand, J.E.; Lipkowski, A.W.; Carr, D.B. Spinal antinociceptive effects of AA501, a novel chimeric peptide with opioid receptor agonist and tachykinin receptor antagonist moieties. Eur. J. Pharmacol.,  2004, 488(1-3), 91-99.
[http://dx.doi.org/10.1016/j.ejphar.2004.02.023] [PMID: 15044040] 
[211] 
Dyniewicz, J.; Lipiński, P.F.J.; Kosson, P.; Leśniak, A.; Bochyńska-Czyż, M.; Muchowska, A.; Tourwé, D.; Ballet, S.; Misicka, A.; Lipkowski, A.W. Hydrazone linker as a useful tool for preparing chimeric peptide/nonpeptide bifunctional compounds. ACS Med. Chem. Lett.,  2016, 8(1), 73-77.
[http://dx.doi.org/10.1021/acsmedchemlett.6b00381] [PMID: 28105278] 
[212] 
Yamamoto, T.; Nair, P.; Jacobsen, N.E.; Kulkarni, V.; Davis, P.; Ma, S.W.; Navratilova, E.; Yamamura, H.I.; Vanderah, T.W.; Porreca, F.; Lai, J.; Hruby, V.J. Biological and conformational evaluation of bifunctional compounds for opioid receptor agonists and neurokinin 1 receptor antagonists possessing two penicillamines. J. Med. Chem.,  2010, 53(15), 5491-5501.
[http://dx.doi.org/10.1021/jm100157m] [PMID: 20617791] 
[213] 
Nair, P.; Yamamoto, T.; Largent-Milnes, T.M.; Cowell, S.; Kulkarni, V.; Moye, S.; Navratilova, E.; Davis, P.; Ma, S.W.; Vanderah, T.W.; Lai, J.; Porreca, F.; Hruby, V.J. Truncation of the peptide sequence in bifunctional ligands with mu and delta opioid receptor agonist and neurokinin 1 receptor antagonist activities. Bioorg. Med. Chem. Lett.,  2013, 23(17), 4975-4978.
[http://dx.doi.org/10.1016/j.bmcl.2013.06.065] [PMID: 23899615] 
[214] 
Nair, P.; Yamamoto, T.; Cowell, S.; Kulkarni, V.; Moye, S.; Navratilova, E.; Davis, P.; Ma, S.W.; Vanderah, T.W.; Lai, J.; Porreca, F.; Hruby, V.J. Discovery of tripeptide-derived multifunctional ligands possessing delta/mu opioid receptor agonist and neurokinin 1 receptor antagonist activities. Bioorg. Med. Chem. Lett.,  2015, 25(17), 3716-3720.
[http://dx.doi.org/10.1016/j.bmcl.2015.06.030] [PMID: 26212775] 
[215] 
Schiller, P.W.; Nguyen, T.M.D.; Chung, N.N.; Dionne, G.; Martel, R. Peripheral antinociceptive effect of an extremely mu-selective polar dermorphin analog (DALDA). Prog. Clin. Biol. Res.,  1990, 328, 53-56.
[PMID: 2154816] 
[216] 
Giri, A.K.; Apostol, C.R.; Wang, Y.; Forte, B.L.; Largent-Milnes, T.M.; Davis, P.; Rankin, D.; Molnar, G.; Olson, K.M.; Porreca, F.; Vanderah, T.W.; Hruby, V.J. Discovery of novel multifunctional ligands with μ/δ opioid agonist/neurokinin-1 (NK1) antagonist activities for the treatment of pain. J. Med. Chem.,  2015, 58(21), 8573-8583.
[http://dx.doi.org/10.1021/acs.jmedchem.5b01170] [PMID: 26465170] 
[217] 
Kowalczyk, A.; Kleczkowska, P.; Rękawek, M.; Kulik, K.; Lesniak, A.; Erdei, A.; Borics, A.; Martin, C.; Pawlik, K.; Lipkowski, A.W.; Benyhe, S.; Makulska-Nowak, H.; Ballet, S.; Bujalska-Zadrozny, M. Biological evaluation and molecular docking studies of AA3052, a compound containing a μ-selective opioid peptide agonist DALDA and d-Phe-Phe-d-Phe-Leu-Leu-NH2, a substance P analogue. Eur. J. Pharm. Sci.,  2016, 93, 11-20.
[http://dx.doi.org/10.1016/j.ejps.2016.07.009] [PMID: 27423260] 
[218] 
Schiller, P.W. Opioid peptide-derived analgesics. AAPS J.,  2005, 7(3), E560-E565.
[http://dx.doi.org/10.1208/aapsj070356] [PMID: 16353933] 
[219] 
Betti, C.; Starnowska, J.; Mika, J.; Dyniewicz, J.; Frankiewicz, L.; Novoa, A.; Bochynska, M.; Keresztes, A.; Kosson, P.; Makuch, W.; Van Duppen, J.; Chung, N.N.; Vanden Broeck, J.; Lipkowski, A.W.; Schiller, P.W.; Janssens, F.; Ceusters, M.; Sommen, F.; Meert, T.; Przewlocka, B.; Tourwé, D.; Ballet, S. Dual alleviation of acute and neuropathic pain by fused opioid agonist-neurokinin 1 antagonist peptidomimetics. ACS Med. Chem. Lett.,  2015, 6(12), 1209-1214.
[http://dx.doi.org/10.1021/acsmedchemlett.5b00359] [PMID: 26713106] 
[220] 
Ballet, S.; Feytens, D.; Buysse, K.; Chung, N.N.; Lemieux, C.; Tumati, S.; Keresztes, A.; Van Duppen, J.; Lai, J.; Varga, E.; Porreca, F.; Schiller, P.W.; Vanden Broeck, J.; Tourwé, D. Design of novel neurokinin 1 receptor antagonists based on conformationally constrained aromatic amino acids and discovery of a potent chimeric opioid agonist-neurokinin 1 receptor antagonist. J. Med. Chem.,  2011, 54(7), 2467-2476.
[http://dx.doi.org/10.1021/jm1016285] [PMID: 21413804] 
[221] 
Guillemyn, K.; Kleczkowska, P.; Novoa, A.; Vandormael, B.; Van den Eynde, I.; Kosson, P.; Asim, M.F.; Schiller, P.W.; Spetea, M.; Lipkowski, A.W.; Tourwé, D.; Ballet, S. In vivo antinociception of potent mu opioid agonist tetrapeptide analogues and comparison with a compact opioid agonist-neurokinin 1 receptor antagonist chimera. Mol. Brain,  2012, 5, 4.
[http://dx.doi.org/10.1186/1756-6606-5-4] [PMID: 22289619] 
[222] 
Guillemyn, K.; Kleczkowska, P.; Lesniak, A.; Dyniewicz, J.; Van der Poorten, O.; Van den Eynde, I.; Keresztes, A.; Varga, E.; Lai, J.; Porreca, F.; Chung, N.N.; Lemieux, C.; Mika, J.; Rojewska, E.; Makuch, W.; Van Duppen, J.; Przewlocka, B.; Vanden Broeck, J.; Lipkowski, A.W.; Schiller, P.W.; Tourwé, D.; Ballet, S. Synthesis and biological evaluation of compact, conformationally constrained bifunctional opioid agonist - neurokinin-1 antagonist peptidomimetics. Eur. J. Med. Chem.,  2015, 92, 64-77.
[http://dx.doi.org/10.1016/j.ejmech.2014.12.033] [PMID: 25544687] 
[223] 
Starnowska, J.; Costante, R.; Guillemyn, K.; Popiolek-Barczyk, K.; Chung, N.N.; Lemieux, C.; Keresztes, A.; Van Duppen, J.; Mollica, A.; Streicher, J.; Vanden Broeck, J.; Schiller, P.W.; Tourwé, D.; Mika, J.; Ballet, S.; Przewlocka, B. Analgesic properties of opioid/nk1 multitarget ligands with distinct in vitro profiles in naive and chronic constriction injury mice. ACS Chem. Neurosci.,  2017, 8(10), 2315-2324.
[http://dx.doi.org/10.1021/acschemneuro.7b00226] [PMID: 28699350] 
[224] 
Bhogal, N.; Donnelly, D.; Findlay, J.B.C. The ligand binding site of the neurokinin 2 receptor. Site-directed mutagenesis and identification of neurokinin A binding residues in the human neurokinin 2 receptor. J. Biol. Chem.,  1996, 271(25), 15298-15298.
[http://dx.doi.org/10.1074/jbc.271.25.15298] [PMID: 8663137] 
[225] 
Greenfeder, S.; Cheewatrakoolpong, B.; Anthes, J.; Billah, M.; Egan, R.W.; Brown, J.E.; Murgolo, N.J. Two related neurokinin-1 receptor antagonists have overlapping but different binding sites. Bioorg. Med. Chem.,  1998, 6(2), 189-194.
[http://dx.doi.org/10.1016/S0968-0896(97)10019-0] [PMID: 9547942] 
[226] 
Malherbe, P.; Bissantz, C.; Marcuz, A.; Kratzeisen, C.; Zenner, M.T.; Wettstein, J.G.; Ratni, H.; Riemer, C.; Spooren, W. Me-talnetant and osanetant interact within overlapping but not identical binding pockets in the human tachykinin neurokinin 3 receptor transmembrane domains. Mol. Pharmacol.,  2008, 73(6), 1736-1750.
[http://dx.doi.org/10.1124/mol.107.042754] [PMID: 18308898] 
[227] 
Turcatti, G.; Zoffmann, S.; Lowe, J.A., III; Drozda, S.E.; Chassaing, G.; Schwartz, T.W.; Chollet, A. Characterization of non-peptide antagonist and peptide agonist binding sites of the NK1 receptor with fluorescent ligands. J. Biol. Chem.,  1997, 272(34), 21167-21175.
[http://dx.doi.org/10.1074/jbc.272.34.21167] [PMID: 9261122] 
[228] 
Vedani, A.; Briem, H.; Dobler, M.; Dollinger, H.; McMasters, D.R. Multiple-conformation and protonation-state representation in 4D-QSAR: the neurokinin-1 receptor system. J. Med. Chem.,  2000, 43(23), 4416-4427.
[http://dx.doi.org/10.1021/jm000986n] [PMID: 11087566] 
[229] 
Vedani, A.; Dobler, M. 5D-QSAR: the key for simulating induced fit? J. Med. Chem.,  2002, 45(11), 2139-2149.
[http://dx.doi.org/10.1021/jm011005p] [PMID: 12014952] 
[230] 
Poulsen, A.; Liljefors, T.; Gundertofte, K.; Bjørnholm, B. A pharmacophore model for NK2 antagonist comprising compounds from several structurally diverse classes. J. Comput. Aided Mol. Des.,  2002, 16(4), 273-286.
[http://dx.doi.org/10.1023/A:1020220306702] [PMID: 12400857] 
[231] 
Lowe, J.A.; Drozda, S.E.; Snider, R.M.; Longo, K.P.; Zorn, S.H.; Morrone, J.; Jackson, E.R.; McLean, S.; Bryce, D.K.; Bordner, J.; Nagahisa, A.; Kanai, Y.; Suga, O.; Tsuchiya, M. The discovery of (2S,3S)-cis-2-(diphenylmethyl)-N-(2-methoxyphenyl)-methyl-1-azabicyclo[2.2.2]octan-3-amine as a novel, nonpeptide substance-P antagonist. J. Med. Chem.,  1992, 35(25), 4768-4768.
[http://dx.doi.org/10.1021/jm00103a022] 
[232] 
Lowe, J.A.; Ewing, F.E.; Snider, R.M.; Longo, K.P.; Constantine, J.W.; Lebel, W.S.; Woody, H.A.; Bordner, J. 2-aryl-1-azabicyclo[2.2.2]octanes as novel nonpeptide substance-P antagonists. Bioorg. Med. Chem. Lett.,  1994, 4(6), 839-842.
[http://dx.doi.org/10.1016/S0960-894X(01)80859-3] 
[233] 
Lewis, R.T.; Macleod, A.M.; Merchant, K.J.; Kelleher, F.; Sanderson, I.; Herbert, R.H.; Cascieri, M.A.; Sadowski, S.; Ball, R.G.; Hoogsteen, K. Tryptophan-derived NK1 antagonists: conformationally constrained heterocyclic bioisosteres of the ester linkage. J. Med. Chem.,  1995, 38(6), 923-933.
[http://dx.doi.org/10.1021/jm00006a011] [PMID: 7699709] 
[234] 
Takeuchi, Y.; Shands, E.F.B.; Beusen, D.D.; Marshall, G.R. Derivation of a three-dimensional pharmacophore model of substance P antagonists bound to the neurokinin-1 receptor. J. Med. Chem.,  1998, 41(19), 3609-3623.
[http://dx.doi.org/10.1021/jm9700171] [PMID: 9733486] 
[235] 
Poulsen, A.; Bjørnholm, B.; Gundertofte, K.; Pogozheva, I.D.; Liljefors, T. Pharmacophore and receptor models for neurokinin receptors. J. Comput. Aided Mol. Des.,  2003, 17(11), 765-783.
[http://dx.doi.org/10.1023/B:JCAM.0000017497.58165.d8] [PMID: 15072436] 
[236] 
Geldenhuys, W.J.; Kuzenko, S.R.; Simmons, M.A. Virtual screening to identify novel antagonists for the G protein-coupled NK3 receptor. J. Med. Chem.,  2010, 53(22), 8080-8088.
[http://dx.doi.org/10.1021/jm1010012] [PMID: 21047106] 
[237] 
Geldenhuys, W.J.; Simmons, M.A. 3D-Quantitative structure-activity relationship and docking studies of the tachykinin NK3 receptor. Bioorg. Med. Chem. Lett.,  2011, 21(24), 7405-7411.
[http://dx.doi.org/10.1016/j.bmcl.2011.10.014] [PMID: 22056747] 
[238] 
Ito, F.; Kondo, H.; Nakane, M.; Shimada, K.; Lowe, J.A., III; Rosen, T.J. Quinuclidine derivatives. U.S. Patent 5,807,867. 1998.
[239] 
Tsuchiya, M.; Fujiwara, Y.; Kanai, Y.; Mizutani, M.; Shimada, K.; Suga, O.; Ueda, S.; Watson, J.W.; Nagahisa, A. Anti-emetic activity of the novel nonpeptide tachykinin NK1 receptor antagonist ezlopitant (CJ-11,974) against acute and delayed cisplatin-induced emesis in the ferret. Pharmacology,  2002, 66(3), 144-152.
[http://dx.doi.org/10.1159/000063796] [PMID: 12372904] 
[240] 
Prakash, C.; O’Donnell, J.; Khojasteh-Bakht, S.C. Metabolism, pharmacokinetics, and excretion of a nonpeptidic substance P receptor antagonist, ezlopitant, in normal healthy male volunteers: characterization of polar metabolites by chemical derivatization with dansyl chloride. Drug Metab. Dispos.,  2007, 35(7), 1071-1080.
[http://dx.doi.org/10.1124/dmd.107.015362] [PMID: 17431029] 
[241] 
Bountra, C.; Bunce, K.; Dale, T.; Gardner, C.; Jordan, C.; Twissell, D.; Ward, P. Anti-emetic profile of a non-peptide neurokinin NK1 receptor antagonist, CP-99,994, in ferrets. Eur. J. Pharmacol.,  1993, 249(1), R3-R4.
[http://dx.doi.org/10.1016/0014-2999(93)90673-6] [PMID: 7506663] 
[242] 
Sun, X.; Xu, L.; Guo, F.; Luo, W.; Gao, S.; Luan, X. Neurokinin-1 receptor blocker CP-99 994 improved emesis induced by cisplatin via regulating the activity of gastric distention responsive neurons in the dorsal motor nucleus of vagus and enhancing gastric motility in rats. Neurogastroenterol. Motil.,  2017, 29(10), 1-11.
[http://dx.doi.org/10.1111/nmo.13096] [PMID: 28464353] 
[243] 
Alvaro, G.; Di Fabio, R.; Maragni, P.; Tampieri, M.; Tranquillini, M.E.  Chemical compounds. WO 2002032867,. 2002.
[244] 
Ratti, E.; Bellew, K.; Bettica, P.; Bryson, H.; Zamuner, S.; Archer, G.; Squassante, L.; Bye, A.; Trist, D.; Krishnan, K.R.; Fernandes, S. Results from 2 randomized, double-blind, placebo-controlled studies of the novel NK1 receptor antagonist casopitant in patients with major depressive disorder. J. Clin. Psychopharmacol.,  2011, 31(6), 727-733.
[http://dx.doi.org/10.1097/JCP.0b013e31823608ca] [PMID: 22020354] 
[245] 
Khojasteh, A.; Khojasteh, A.; Thornburg, B.G.; Maher, K.R. Casopitant: a new warrior in the antiemetic crusade. Expert Opin. Pharmacother.,  2009, 10(8), 1367-1376.
[http://dx.doi.org/10.1517/14656560902953746] [PMID: 19445564] 
[246] 
Adams, L.M.; Johnson, B.; Murray, S. A pharmacokinetic, pharmacodynamic, and safety study of intravenous cyclophosphamide with an oral casopitant antiemetic regimen in cancer patients. Clin. Pharmacol. Drug Dev.,  2014, 3(2), 93-100.
[http://dx.doi.org/10.1002/cpdd.57] [PMID: 27128454] 
[247] 
Ratti, E.; Bettica, P.; Alexander, R.; Archer, G.; Carpenter, D.; Evoniuk, G.; Gomeni, R.; Lawson, E.; Lopez, M.; Millns, H.; Rabiner, E.A.; Trist, D.; Trower, M.; Zamuner, S.; Krishnan, R.; Fava, M. Full central neurokinin-1 receptor blockade is required for efficacy in depression: evidence from orvepitant clinical studies. J. Psychopharmacol. (Oxford),  2013, 27(5), 424-434.
[http://dx.doi.org/10.1177/0269881113480990] [PMID: 23539641] 
[248] 
Duffy, R.A.; Morgan, C.; Naylor, R.; Higgins, G.A.; Varty, G.B.; Lachowicz, J.E.; Parker, E.M. Rolapitant (SCH 619734): a potent, selective and orally active neurokinin NK1 receptor antagonist with centrally-mediated antiemetic effects in ferrets. Pharmacol. Biochem. Behav.,  2012, 102(1), 95-100.
[http://dx.doi.org/10.1016/j.pbb.2012.03.021] [PMID: 22497992] 
[249] 
Heo, Y.A.; Deeks, E.D. Rolapitant: a review in chemotherapy-induced nausea and vomiting. Drugs,  2017, 77(15), 1687-1694.
[http://dx.doi.org/10.1007/s40265-017-0816-z] [PMID: 28929404] 
[250] 
Clark-Snow, R.; Nagy, C.; Arora, S.; Poma, A.; Navari, R. Rolapitant, a novel NK-1 receptor antagonist (NK1-RA), phase 3 trials results in the prevention of chemotherapy-induced nausea and vomiting (CINV) in subjects receiving highly or moderately emetogenic chemotherapy (HEC and MEC). Oncol. Nurs. Forum,  2015, 42(2), E222-E223.
[251] 
Haab, F.; Braticevici, B.; Krivoborodov, G.; Palmas, M.; Zufferli Russo, M.; Pietra, C. Efficacy and safety of repeated dosing of netupitant, a neurokinin-1 receptor antagonist, in treating overactive bladder. Neurourol. Urodyn.,  2014, 33(3), 335-340.
[http://dx.doi.org/10.1002/nau.22406] [PMID: 23765630] 
[252] 
Rizzi, A.; Campi, B.; Camarda, V.; Molinari, S.; Cantoreggi, S.; Regoli, D.; Pietra, C.; Calo’, G. In vitro and in vivo pharmacological characterization of the novel NK1 receptor selective antagonist Netupitant. Peptides,  2012, 37(1), 86-97.
[http://dx.doi.org/10.1016/j.peptides.2012.06.010] [PMID: 22732666] 
[253] 
Hoffmann, T.; Bös, M.; Stadler, H.; Schnider, P.; Hunkeler, W.; Godel, T.; Galley, G.; Ballard, T.M.; Higgins, G.A.; Poli, S.M.; Sleight, A.J. Design and synthesis of a novel, achiral class of highly potent and selective, orally active neurokinin-1 receptor antagonists. Bioorg. Med. Chem. Lett.,  2006, 16(5), 1362-1365.
[http://dx.doi.org/10.1016/j.bmcl.2005.11.047] [PMID: 16332435] 
[254] 
Keating, G.M. Netupitant/palonosetron: a review in the prevention of chemotherapy-induced nausea and vomiting. Drugs,  2015, 75(18), 2131-2141.
[http://dx.doi.org/10.1007/s40265-015-0512-9] [PMID: 26613606] 
[255] 
Abramovitz, R.B.; Gaertner, K.M. The role of netupitant and palonosetron in chemotherapy-induced nausea and vomiting. J. Oncol. Pharm. Pract.,  2016, 22(3), 477-484.
[http://dx.doi.org/10.1177/1078155215581525] [PMID: 25914408] 
[256] 
Palea, S.; Guilloteau, V.; Rekik, M.; Lovati, E.; Guerard, M.; Guardia, M.A.; Lluel, P.; Pietra, C.; Yoshiyama, M. Netupitant, a potent and highly selective NK1 receptor antagonist, alleviates acetic acid-induced bladder overactivity in anesthetized guinea-pigs. Front. Pharmacol.,  2016, 7, 234.
[http://dx.doi.org/10.3389/fphar.2016.00234] [PMID: 27540361] 
[257] 
Cutrer, F.M.; Moussaoui, S.; Garret, C.; Moskowitz, M.A. The non-peptide neurokinin-1 antagonist, RPR 100893, decreases c-fos expression in trigeminal nucleus caudalis following noxious chemical meningeal stimulation. Neuroscience,  1995, 64(3), 741-750.
[http://dx.doi.org/10.1016/0306-4522(94)00428-8] [PMID: 7536309] 
[258] 
Venkova, K.; Sutkowski-Markmann, D.M.; Greenwood-Van Meerveld, B. Peripheral activity of a new NK1 receptor antagonist TAK-637 in the gastrointestinal tract. J. Pharmacol. Exp. Ther.,  2002, 300(3), 1046-1052.
[http://dx.doi.org/10.1124/jpet.300.3.1046] [PMID: 11861814] 
[259] 
Altamura, M. Tachykinin NK2 receptor antagonists. A patent review (2006 - 2010). Expert Opin. Ther. Pat.,  2012, 22(1), 57-77.
[http://dx.doi.org/10.1517/13543776.2012.645537] [PMID: 22149761] 
[260] 
Tanaka, T.; Tanaka, A.; Nakamura, A.; Matsushita, K.; Imanishi, A.; Matsumoto-Okano, S.; Inatomi, N.; Miura, K.; Toyoda, M.; Mizojiri, G.; Tsukimi, Y. Effects of TAK-480, a novel tachykinin NK(2)-receptor antagonist, on visceral hypersensitivity in rabbits and ricinoleic acid-induced defecation in guinea pigs. J. Pharmacol. Sci.,  2012, 120(1), 15-25.
[http://dx.doi.org/10.1254/jphs.12085FP] [PMID: 22893394] 
[261] 
Efficacy, safety and tolerability of dnk333 (25 and 100 mg
 bid) in women with diarrhea-predominant irritable bowel
 syndrome (IBS-D) (CDNK333B2201). Available at: https://clinicaltrials.gov/ct2/show?term=DNK333&rank=3 (Accessed Date: 25 Febuary, 2018)
[262] 
 Safety and efficacy of DNK333 in atopic dermatitis patients. Available at:  https://clinicaltrials.gov/ct2/show/NCT01033097?term=DNK333&rank=2 (Accessed Date: 25 Febuary, 2018)
[263] 
Daoui, S.; Cui, Y.Y.; Lagente, V.; Emonds-Alt, X.; Advenier, C. A tachykinin NK3 receptor antagonist, SR 142801 (osanetant), prevents substance P-induced bronchial hyperreactivity in guinea-pigs. Pulm. Pharmacol. Ther.,  1997, 10(5-6), 261-270.
[http://dx.doi.org/10.1006/pupt.1998.0104] [PMID: 9778489] 
[264] 
Dawson, L.A.; Cato, K.J.; Scott, C.; Watson, J.M.; Wood, M.D.; Foxton, R.; de la Flor, R.; Jones, G.A.; Kew, J.N.C.; Cluderay, J.E.; Southam, E.; Murkitt, G.S.; Gartlon, J.; Pemberton, D.J.; Jones, D.N.C.; Davies, C.H.; Hagan, J. In vitro and in vivo characterization of the non-peptide NK3 receptor antagonist SB-223412 (talnetant): potential therapeutic utility in the treatment of schizophrenia. Neuropsychopharmacology,  2008, 33(7), 1642-1652.
[http://dx.doi.org/10.1038/sj.npp.1301549] [PMID: 17728699] 
[265] 
Malherbe, P.; Ballard, T.M.; Ratni, H. Tachykinin neurokinin 3 receptor antagonists: a patent review (2005 - 2010). Expert Opin. Ther. Pat.,  2011, 21(5), 637-655.
[http://dx.doi.org/10.1517/13543776.2011.568482] [PMID: 21417773] 
[266] 
Griebel, G.; Beeské, S. Is there still a future for neurokinin 3 receptor antagonists as potential drugs for the treatment of psychiatric diseases? Pharmacol. Ther.,  2012, 133(1), 116-123.
[http://dx.doi.org/10.1016/j.pharmthera.2011.09.007] [PMID: 21963368] 
[267] 
Xu, H.; Li, J.; Webber, L.; Kakkar, R.; Chen, Y.; Al-Huniti, N. Population pharmacokinetic and pharmacodynamic modeling of AZD4901 and simulation to support dose selection for the phase 2a study. J. Clin. Pharmacol.,  2016, 56(8), 999-1008.
[http://dx.doi.org/10.1002/jcph.680] [PMID: 26626581] 
[268] 
Xiong, H.; Kang, J.; Woods, J.M.; McCauley, J.P., Jr; Koether, G.M.; Albert, J.S.; Hinkley, L.; Li, Y.; Gadient, R.A.; Simpson, T.R. Synthesis and SAR of sulfoxide substituted carboxyquinolines as NK3 receptor antagonists. Bioorg. Med. Chem. Lett.,  2011, 21(6), 1896-1899.
[http://dx.doi.org/10.1016/j.bmcl.2010.11.003] [PMID: 21320776] 
[269] 
Khanzhin, N.; Simonsen, K.B.; Nielsen, S.M.; Juhl, K. Azaisoquinolinone derivatives as NK3 antagonists. U.S. Patent 2011/0224247 A1, . 2011.
[270] 
Hoveyda, H.; Roy, M.-O.; Fraser, G.L.; Dutheuil, G. Novel
 NK-3 receptor selective antagonist compounds, pharmaceutical
 composition and methods for use in NK-3 receptors
 mediated disorders. WO 2011121137 A1,. 2011.
[271] 
Dawson, L.A.; Langmead, C.J.; Dada, A.; Watson, J.M.; Wu, Z.; de la Flor, R.; Jones, G.A.; Cluderay, J.E.; Southam, E.; Murkitt, G.S.; Hill, M.D.; Jones, D.N.C.; Davies, C.H.; Hagan, J.J.; Smith, P.W. In vitro and in vivo comparison of two non-peptide tachykinin NK3 receptor antagonists: Improvements in efficacy achieved through enhanced brain penetration or altered pharmacological characteristics. Eur. J. Pharmacol.,  2010, 627(1-3), 106-114.
[http://dx.doi.org/10.1016/j.ejphar.2009.10.054] [PMID: 19879867] 
[272] 
Yamamoto, K.; Okazaki, S.; Ohno, H.; Matsuda, F.; Ohkura, S.; Maeda, K.; Fujii, N.; Oishi, S. Development of novel NK3 receptor antagonists with reduced environmental impact. Bioorg. Med. Chem.,  2016, 24(16), 3494-3500.
[http://dx.doi.org/10.1016/j.bmc.2016.05.054] [PMID: 27298001] 
[273] 
Ratni, H.; Ballard, T.M.; Bissantz, C.; Hoffmann, T.; Jablonski, P.; Knoflach, F.; Knust, H.; Malherbe, P.; Nettekoven, M.; Patiny-Adam, A.; Riemer, C.; Schmitt, M.; Spooren, W. Rational design of novel pyrrolidine derivatives as orally active neurokinin-3 receptor antagonists. Bioorg. Med. Chem. Lett.,  2010, 20(22), 6735-6738.
[http://dx.doi.org/10.1016/j.bmcl.2010.08.138] [PMID: 20850972] 
[274] 
Wu, Z.; Graybill, T.L.; Zeng, X.; Platchek, M.; Zhang, J.; Bodmer, V.Q.; Wisnoski, D.D.; Deng, J.; Coppo, F.T.; Yao, G.; Tamburino, A.; Scavello, G.; Franklin, G.J.; Mataruse, S.; Bedard, K.L.; Ding, Y.; Chai, J.; Summerfield, J.; Centrella, P.A.; Messer, J.A.; Pope, A.J.; Israel, D.I. Cell-based selection expands the utility of dna-encoded small-molecule library technology to cell surface drug targets: identification of novel antagonists of the NK3 tachykinin receptor. ACS Comb. Sci.,  2015, 17(12), 722-731.
[http://dx.doi.org/10.1021/acscombsci.5b00124] [PMID: 26562224] 
[275] 
Hoveyda, H.R.; Roy, M.O.; Blanc, S.; Noël, S.; Salvino, J.M.; Ator, M.A.; Fraser, G. Discovery of 3-aryl-5-acylpiperazinyl-pyrazoles as antagonists to the NK3 receptor. Bioorg. Med. Chem. Lett.,  2011, 21(7), 1991-1996.
[http://dx.doi.org/10.1016/j.bmcl.2011.02.033] [PMID: 21376585] 
[276] 
Peters, J.U.; Hoffmann, T.; Schnider, P.; Stadler, H.; Koblet, A.; Alker, A.; Poli, S.M.; Ballard, T.M.; Spooren, W.; Steward, L.; Sleight, A.J. Discovery of potent, balanced and orally active dual NK1/NK3 receptor ligands. Bioorg. Med. Chem. Lett.,  2010, 20(11), 3405-3408.
[http://dx.doi.org/10.1016/j.bmcl.2010.04.008] [PMID: 20430616] 
[277] 
Malherbe, P.; Knoflach, F.; Hernandez, M.C.; Hoffmann, T.; Schnider, P.; Porter, R.H.; Wettstein, J.G.; Ballard, T.M.; Spooren, W.; Steward, L. Characterization of RO4583298 as a novel potent, dual antagonist with in vivo activity at tachykinin NK1 and NK3 receptors. Br. J. Pharmacol.,  2011, 162(4), 929-946.
[http://dx.doi.org/10.1111/j.1476-5381.2010.01096.x] [PMID: 21039418] 
[278] 
Hanessian, S.; Jennequin, T.; Boyer, N.; Babonneau, V.; Soma, U.; Mannoury la Cour, C.; Millan, M.J.; De Nanteuil, G. Design, Synthesis, and Optimization of Balanced Dual NK1/NK3 Receptor Antagonists. ACS Med. Chem. Lett.,  2014, 5(5), 550-555.
[http://dx.doi.org/10.1021/ml400528y] [PMID: 24900878] 
[279] 
Hanessian, S.; Babonneau, V.; Boyer, N.; Mannoury la Cour, C.; Millan, M.J.; De Nanteuil, G. Design and synthesis of potential dual NK(1)/NK(3) receptor antagonists. Bioorg. Med. Chem. Lett.,  2014, 24(2), 510-514.
[http://dx.doi.org/10.1016/j.bmcl.2013.12.033] [PMID: 24374277] 
[280] 
Walpole, C.S.J.; Brown, M.C.S.; James, I.F.; Campbell, E.A.; McIntyre, P.; Docherty, R.; Ko, S.; Hedley, L.; Ewan, S.; Buchheit, K.H.; Urban, L.A. Comparative, general pharmacology of SDZ NKT 343, a novel, selective NK1 receptor antagonist. Br. J. Pharmacol.,  1998, 124(1), 83-92.
[http://dx.doi.org/10.1038/sj.bjp.0701806] [PMID: 9630347] 
[281] 
Pham, T.M.; Couture, R. Inhibitory action of (+/-)CP-96,345 on the cardiovascular responses to intrathecal substance P and neuropeptide K in the conscious freely moving rat. Naunyn Schmiedebergs Arch. Pharmacol.,  1993, 347(1), 34-41.
[http://dx.doi.org/10.1007/BF00168769] [PMID: 7680439] 
[282] 
Sundqvist, M.; Kristensson, E.; Adolfsson, R.; Leffler, A.; Ahlstedt, I.; Engberg, S.; Drmota, T.; Sigfridsson, K.; Jussila, R.; de Verdier, J.; Novén, A.; Johansson, A.; Påhlman, I.; von Mentzer, B.; Lindström, E. Senktide-induced gerbil foot tapping behaviour is blocked by selective tachykinin NK1 and NK3 receptor antagonists. Eur. J. Pharmacol.,  2007, 577(1-3), 78-86.
[http://dx.doi.org/10.1016/j.ejphar.2007.08.042] [PMID: 17920583] 
[283] 
Ashwood, V.A.; Field, M.J.; Horwell, D.C.; Julien-Larose, C.; Lewthwaite, R.A.; McCleary, S.; Pritchard, M.C.; Raphy, J.; Singh, L. Utilization of an intramolecular hydrogen bond to increase the CNS penetration of an NK(1) receptor antagonist. J. Med. Chem.,  2001, 44(14), 2276-2285.
[http://dx.doi.org/10.1021/jm010825z] [PMID: 11428921] 
[284] 
Alex, A.; Millan, D.S.; Perez, M.; Wakenhut, F.; Whitlock, G.A. Intramolecular hydrogen bonding to improve membrane permeability and absorption in beyond rule of five chemical space. MedChemComm,  2011, 2(7), 669-674.
[http://dx.doi.org/10.1039/c1md00093d] 
[285] 
Krämer, S.D.; Aschmann, H.E.; Hatibovic, M.; Hermann, K.F.; Neuhaus, C.S.; Brunner, C.; Belli, S. When barriers ignore the “rule-of-five”. Adv. Drug Deliv. Rev.,  2016, 101, 62-74.
[http://dx.doi.org/10.1016/j.addr.2016.02.001] [PMID: 26877103] 
[286] 
Rankovic, Z. CNS drug design: balancing physicochemical properties for optimal brain exposure. J. Med. Chem.,  2015, 58(6), 2584-2608.
[http://dx.doi.org/10.1021/jm501535r] [PMID: 25494650] 
[287] 
Singh, L.; Field, M.J.; Hughes, J.; Kuo, B.S.; Suman-Chauhan, N.; Tuladhar, B.R.; Wright, D.S.; Naylor, R.J. The tachykinin NK1 receptor antagonist PD 154075 blocks cisplatin-induced delayed emesis in the ferret. Eur. J. Pharmacol.,  1997, 321(2), 209-216.
[http://dx.doi.org/10.1016/S0014-2999(96)00950-8] [PMID: 9063690] 
[288] 
Ettorre, A.; D’Andrea, P.; Mauro, S.; Porcelloni, M.; Rossi, C.; Altamura, M.; Catalioto, R.M.; Giuliani, S.; Maggi, C.A.; Fattori, D. hNK2 receptor antagonists. The use of intramolecular hydrogen bonding to increase solubility and membrane permeability. Bioorg. Med. Chem. Lett.,  2011, 21(6), 1807-1809.
[http://dx.doi.org/10.1016/j.bmcl.2011.01.074] [PMID: 21320781] 
[289] 
Sarau, H.M.; Griswold, D.E.; Potts, W.; Foley, J.J.; Schmidt, D.B.; Webb, E.F.; Martin, L.D.; Brawner, M.E.; Elshourbagy, N.A.; Medhurst, A.D.; Giardina, G.A.M.; Hay, D.W.P. Nonpeptide tachykinin receptor antagonists: I. Pharmacological and pharmacokinetic characterization of SB 223412, a novel, potent and selective neurokinin-3 receptor antagonist. J. Pharmacol. Exp. Ther.,  1997, 281(3), 1303-1311.
[PMID: 9190866] 
[290] 
Sarau, H.M.; Griswold, D.E.; Bush, B.; Potts, W.; Sandhu, P.; Lundberg, D.; Foley, J.J.; Schmidt, D.B.; Webb, E.F.; Martin, L.D.; Legos, J.J.; Whitmore, R.G.; Barone, F.C.; Medhurst, A.D.; Luttmann, M.A.; Giardina, G.A.M.; Hay, D.W.P. Nonpeptide tachykinin receptor antagonists. II. Pharmacological and pharmacokinetic profile of SB-222200, a central nervous system penetrant, potent and selective NK-3 receptor antagonist. J. Pharmacol. Exp. Ther.,  2000, 295(1), 373-381.
[PMID: 10992004] 
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DOI https://dx.doi.org/10.2174/0929867325666180913095918	Print ISSN 0929-8673
Publisher Name Bentham Science Publisher	Online ISSN 1875-533X
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