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Medicinal Chemistry

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ISSN (Print): 1573-4064
ISSN (Online): 1875-6638

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Research Article

New Serotoninergic Ligands Containing Indolic and Methyl Indolic Nuclei: Synthesis and In Vitro Pharmacological Evaluation

Author(s): Elisa Magli, Beatrice Severino*, Angela Corvino, Elisa Perissutti, Francesco Frecentese, Irene Saccone, Flavia Giordano, Marián Castro, José Brea, María I. Loza, Vincenzo Santagada, Giuseppe Caliendo and Ferdinando Fiorino

Volume 16, Issue 4, 2020

Page: [517 - 530] Pages: 14

DOI: 10.2174/1573406415666190613153220

Price: $65

Abstract

Background: Serotonin is an important biogenic amine and is implicated in wideranging physiological and physiopathological processes. Pharmacological manipulation of the serotoninergic system is believed to have a great therapeutic potential.

Objectives: In order to identify selective ligands for 5-HT1A, 5-HT2A and 5-HT2C receptors two series of 4-substituted piperazine derivatives, bearing indolic or methyl indolic nuclei, were synthesized.

Methods: All the compounds, synthesized by standard solution methods, were evaluated for 5- HT1A, 5-HT2A and 5-HT2C receptors. The highest affine and selective compounds have been evaluated also on dopaminergic (D1 and D2) and adrenergic (α1A and α2A) receptors.

Results: Several of the newly synthesized molecules showed affinity in the nanomolar range for 5- HT1A, 5-HT2A and 5-HT2C receptors and moderate to no affinity for other relevant receptors (D1, D2, α1A and α2A).

Conclusion: Compounds 7f and 10a showed a nanomolar affinity towards 5-HT1A with an in vitro pharmacologic profile compatible with antipsychotic drugs.

Keywords: Arylpiperazine derivatives, binding assay, indolic and methyl indolic nuclei, synthesis, serotonin, 5-HT1A, 5-HT2A and 5-HT2C receptor ligands.

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[1]
Fredriksson, R.; Lagerström, M.C.; Lundin, L.G.; Schiöth, H.B. The G-protein-coupled receptors in the human genome form five main families. Phylogenetic analysis, paralogon groups, and fingerprints. Mol. Pharmacol., 2003, 63(6), 1256-1272.
[http://dx.doi.org/10.1124/mol.63.6.1256] [PMID: 12761335]
[2]
Nichols, D.E.; Nichols, C.D. Serotonin receptors. Chem. Rev., 2008, 108(5), 1614-1641.
[http://dx.doi.org/10.1021/cr078224o] [PMID: 18476671]
[3]
Siddiqui, E.J.; Shabbir, M.; Mikhailidis, D.P.; Thompson, C.S.; Mumtaz, F.H. The role of serotonin (5-hydroxytryptamine1A and 1B) receptors in prostate cancer cell proliferation. J. Urol., 2006, 176(4 Pt 1), 1648-1653.
[http://dx.doi.org/10.1016/j.juro.2006.06.087] [PMID: 16952708]
[4]
Jones, B.J.; Blackburn, T.P. The medical benefit of 5-HT research. Pharmacol. Biochem. Behav., 2002, 71(4), 555-568.
[http://dx.doi.org/10.1016/S0091-3057(01)00745-6] [PMID: 11888547]
[5]
Parker, M.A.; Kurrasch, D.M.; Nichols, D.E. The role of lipophilicity in determining binding affinity and functional activity for 5-HT2A receptor ligands. Bioorg. Med. Chem., 2008, 16(8), 4661-4669.
[http://dx.doi.org/10.1016/j.bmc.2008.02.033] [PMID: 18296055]
[6]
Shimada, I.; Maeno, K.; Kazuta, K.; Kubota, H.; Kimizuka, T.; Kimura, Y.; Hatanaka, K.; Naitou, Y.; Wanibuchi, F.; Sakamoto, S.; Tsukamoto, S. Synthesis and structure-activity relationships of a series of substituted 2-(1H-furo[2,3-g]indazol-1-yl)ethylamine derivatives as 5-HT2C receptor agonists. Bioorg. Med. Chem., 2008, 16(4), 1966-1982.
[http://dx.doi.org/10.1016/j.bmc.2007.10.100] [PMID: 18035544]
[7]
López-Rodríguez, M.L.; Ayala, D.; Benhamú, B.; Morcillo, M.J.; Viso, A. Arylpiperazine derivatives acting at 5-HT(1A) receptors. Curr. Med. Chem., 2002, 9(4), 443-469.
[http://dx.doi.org/10.2174/0929867023371030] [PMID: 11945120]
[8]
Fiorino, F.; Perissutti, E.; Severino, B.; Santagada, V.; Cirillo, D.; Terracciano, S.; Massarelli, P.; Bruni, G.; Collavoli, E.; Renner, C.; Caliendo, G. New 5-hydroxytryptamine(1A) receptor ligands containing a norbornene nucleus: synthesis and in vitro pharmacological evaluation. J. Med. Chem., 2005, 48(17), 5495-5503.
[http://dx.doi.org/10.1021/jm050246k] [PMID: 16107148]
[9]
Fiorino, F.; Severino, B.; De Angelis, F.; Perissutti, E.; Frecentese, F.; Massarelli, P.; Bruni, G.; Collavoli, E.; Santagada, V.; Caliendo, G. Synthesis and in-vitro pharmacological evaluation of new 5-HT1A receptor ligands containing a benzotriazinone nucleus. Arch. Pharm. (Weinheim), 2008, 341(1), 20-27.
[http://dx.doi.org/10.1002/ardp.200700151] [PMID: 18072244]
[10]
Frecentese, F.; Fiorino, F.; Perissutti, E.; Severino, B.; Magli, E.; Esposito, A.; De Angelis, F.; Massarelli, P.; Nencini, C.; Viti, B.; Santagada, V.; Caliendo, G. Efficient microwave combinatorial synthesis of novel indolic arylpiperazine derivatives as serotoninergic ligands. Eur. J. Med. Chem., 2010, 45(2), 752-759.
[http://dx.doi.org/10.1016/j.ejmech.2009.11.023] [PMID: 19954866]
[11]
Fiorino, F.; Severino, B.; De Angelis, F.; Perissutti, E.; Magli, E.; Frecentese, F.; Esposito, A.; Massarelli, P.; Nencini, C.; Viti, B.; Santagada, V.; Caliendo, G. Synthesis and in vitro pharmacological evaluation of a new series of 5-HT1A 5-HT2A and 5-HT2C receptor ligands containing a norbornene nucleus. Pharmazie, 2009, 64(9), 555-564.
[PMID: 19827295]
[12]
Fiorino, F.; Severino, B.; De Angelis, F.; Perissutti, E.; Magli, E.; Frecentese, F.; Esposito, A.; Massarelli, P.; Nencini, C.; Santagada, V.; Caliendo, G. New 5-HT(1A) receptor ligands containing a N′-cyanoisonicotinamidine nucleus: Synthesis and in vitro pharmacological evaluation. Bioorg. Med. Chem. Lett., 2010, 20(9), 2978-2982.
[http://dx.doi.org/10.1016/j.bmcl.2010.02.106] [PMID: 20347301]
[13]
Fiorino, F.; Magli, E.; Severino, B.; Corvino, A.; Ciano, A.; Perissutti, E.; Frecentese, F.; Massarelli, P.; Nencini, C.; Santagada, V.; Caliendo, G. Synthesis and in vitro pharmacological evaluation of novel 2-hydroxypropyl-4-arylpiperazine derivatives as serotoninergic ligands. Arch. Pharm. (Weinheim), 2014, 347(10), 698-706.
[http://dx.doi.org/10.1002/ardp.201400174] [PMID: 25113046]
[14]
Fiorino, F.; Magli, E.; Perissutti, E.; Severino, B.; Frecentese, F.; Esposito, A.; De Angelis, F.; Incisivo, G.M.; Massarelli, P.; Nencini, C.; Di Gennaro, E.; Budillon, A.; Di Cintio, A.; Santagada, V.; Caliendo, G. Synthesis of 1-naphtylpiperazine derivatives as serotoninergic ligands and their evaluation as antiproliferative agents. Eur. J. Med. Chem., 2011, 46(6), 2206-2216.
[http://dx.doi.org/10.1016/j.ejmech.2011.03.001] [PMID: 21440338]
[15]
Fiorino, F.; Severino, B.; Magli, E.; Perissutti, E.; Frecentese, F.; Esposito, A.; Incisivo, G.M.; Ciano, A.; Massarelli, P.; Nencini, C.; Santagada, V.; Caliendo, G. New potent 5-HT(2A) receptor ligands containing an N′-cyanopicolinamidine nucleus: Synthesis and in vitro pharmacological evaluation. Eur. J. Med. Chem., 2012, 47(1), 520-529.
[http://dx.doi.org/10.1016/j.ejmech.2011.11.023] [PMID: 22133459]
[16]
Fiorino, F.; Severino, B.; Magli, E.; Ciano, A.; Caliendo, G.; Santagada, V.; Frecentese, F.; Perissutti, E. 5-HT(1A) receptor: An old target as a new attractive tool in drug discovery from central nervous system to cancer. J. Med. Chem., 2014, 57(11), 4407-4426.
[http://dx.doi.org/10.1021/jm400533t] [PMID: 24295064]
[17]
Fiorino, F.; Ciano, A.; Magli, E.; Severino, B.; Corvino, A.; Perissutti, E.; Frecentese, F.; Di Vaio, P.; Izzo, A.A.; Capasso, R.; Massarelli, P.; Nencini, C.; Rossi, I.; Kędzierska, E.; Orzelska-Gòrka, J.; Bielenica, A.; Santagada, V.; Caliendo, G. Synthesis, in vitro and in vivo pharmacological evaluation of serotoninergic ligands containing an isonicotinic nucleus. Eur. J. Med. Chem., 2016, 110, 133-150.
[http://dx.doi.org/10.1016/j.ejmech.2016.01.021] [PMID: 26820556]
[18]
Fiorino, F.; Magli, E.; Kędzierska, E.; Ciano, A.; Corvino, A.; Severino, B.; Perissutti, E.; Frecentese, F.; Di Vaio, P.; Saccone, I.; Izzo, A.A.; Capasso, R.; Massarelli, P.; Rossi, I.; Orzelska-Gòrka, J.; Kotlińska, J.H.; Santagada, V.; Caliendo, G. New 5-HT1A, 5HT2A and 5HT2C receptor ligands containing a picolinic nucleus: Synthesis, in vitro and in vivo pharmacological evaluation. Bioorg. Med. Chem., 2017, 25(20), 5820-5837.
[http://dx.doi.org/10.1016/j.bmc.2017.09.018] [PMID: 28943244]
[19]
Corvino, A.; Fiorino, F.; Severino, B.; Saccone, I.; Frecentese, F.; Perissutti, E.; Di Vaio, P.; Santagada, V.; Caliendo, G.; Magli, E. The role of 5-HT1A receptor in cancer as a new opportunity in medicinal chemistry. Curr. Med. Chem., 2018, 25(27), 3214-3227.
[http://dx.doi.org/10.2174/0929867325666180209141650] [PMID: 29424302]
[20]
Cheng, Y.; Prusoff, W.H. Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction. Biochem. Pharmacol., 1973, 22(23), 3099-3108.
[http://dx.doi.org/dx.doi.org 10.1016/0006-2952(73)90196-2] [PMID: 4202581]
[21]
Huang, J.; He, F.; Huang, M.; Liu, X.; Xiong, Y.; Huang, Y.; Zhu, L.; Yang, Y.; Xu, X.; Yuan, M. Novel naftopidil-related derivatives and their biological effects as alpha1-adrenoceptors antagonists and antiproliferative agents. Eur. J. Med. Chem., 2015, 96, 83-91.
[http://dx.doi.org/10.1016/j.ejmech.2015.04.005] [PMID: 25874333]
[22]
Zlatović, M.V.; Sukalović, V.V.; Schneider, C.; Roglić, G.M. Interaction of arylpiperazine ligands with the hydrophobic part of the 5-HT1A receptor binding site. Bioorg. Med. Chem., 2006, 14(9), 2994-3001.
[http://dx.doi.org/10.1016/j.bmc.2005.12.023] [PMID: 16403641]
[23]
Ngo, T.; Nicholas, T.J.; Chen, J.; Finch, A.M.; Griffith, R. 5-HT1A receptor pharmacophores to screen for off-target activity of α1 adrenoceptor antagonists. J. Comput. Aided Mol. Des., 2013, 27(4), 305-319.
[http://dx.doi.org/10.1007/s10822-013-9647-5] [PMID: 23625023]

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