Abstract
Background: In the past few decades, considerable progress has been made in CNS drug discovery, and various new CNS agents have been developed. Pyrimidine is an important scaffold in the area of medicinal chemistry. Recently, pyrimidine-containing compounds have been successfully designed as potent CNS agents. Substantial research has been carried out on pyrimidine-bearing compounds to treat different disorders of CNS in various animal models.
Methods: Utilizing various databases, including Google Scholar, PubMed, Science Direct, and Web of Science, the literature review was conducted. The specifics of significant articles were discussed with an emphasis on the potency of pyrimidines derivatives possessing CNS activity.
Results: Recent papers indicating pyrimidine derivatives with CNS activity were incorporated into the manuscript. (46) to (50) papers included different pyrimidine derivatives as 5-HT agonist/antagonists, (62) to (67) as adenosine agonist/antagonist, (70) to (75) as anticonvulsant agents, (80) to (83) as cannabinoid receptor agonists, (102) to (103) as nicotinic and (110) as muscarinic receptor agonists. The remaining papers (113) to (114) represented pyrimidine-based molecular imaging agents.
Conclusion: Pyrimidine and its derivatives have been studied in detail to evaluate their efficacy in overcoming multiple central nervous system disorders. The article covers the current updates on pyrimidine-based compounds as potent CNS and molecular imaging agents and will definitely provide a better platform for the development of potent pyrimidine-based CNS drugs in the near future.
Keywords: Pyrimidine, serotonin receptors, adenosine receptors, cannabinoid receptors, acetylcholine receptors, anticonvulsants, heterocycles
Graphical Abstract
[http://dx.doi.org/10.3390/cells10071810] [PMID: 34359979]
[http://dx.doi.org/10.1016/j.trechm.2019.04.009]
[http://dx.doi.org/10.1002/wnan.1695] [PMID: 33470550]
[http://dx.doi.org/10.1002/med.21764] [PMID: 33295676]
[http://dx.doi.org/10.3923/ijbc.2015.148.177]
[http://dx.doi.org/10.3390/ijms22083825] [PMID: 33917090]
[http://dx.doi.org/10.3390/molecules26030771] [PMID: 33540875]
[http://dx.doi.org/10.3390/molecules26133779] [PMID: 34206327]
[http://dx.doi.org/10.1038/s41598-020-65152-4] [PMID: 32424333]
[http://dx.doi.org/10.3390/molecules26196022] [PMID: 34641566]
[http://dx.doi.org/10.1016/j.bioorg.2021.105186] [PMID: 34314914]
[http://dx.doi.org/10.1016/j.bioorg.2020.104555] [PMID: 33376011]
[http://dx.doi.org/10.1016/j.bioorg.2021.104890] [PMID: 33872924]
[http://dx.doi.org/10.1016/j.bmcl.2017.02.036] [PMID: 28259627]
[http://dx.doi.org/10.1016/j.ejmech.2012.12.003] [PMID: 23376247]
[http://dx.doi.org/10.1080/07391102.2020.1759454] [PMID: 32329409]
[http://dx.doi.org/10.1002/cbdv.201800563] [PMID: 30740903]
[http://dx.doi.org/10.1016/j.ejmech.2021.113330] [PMID: 33744688]
[http://dx.doi.org/10.2174/1568026619666191019100711] [PMID: 31648638]
[http://dx.doi.org/10.1016/j.bioorg.2020.104509] [PMID: 33288321]
[http://dx.doi.org/10.1007/s11030-018-9859-7] [PMID: 30027387]
[http://dx.doi.org/10.1021/acsinfecdis.0c00851] [PMID: 33405882]
[http://dx.doi.org/10.1080/15257770.2021.1972310] [PMID: 34470580]
[http://dx.doi.org/10.3109/14756366.2011.557022] [PMID: 21381888]
[http://dx.doi.org/10.1021/jm00274a040] [PMID: 5019576]
[http://dx.doi.org/10.1016/j.bmc.2016.09.030] [PMID: 27687967]
[http://dx.doi.org/10.1021/jm00346a017] [PMID: 6279846]
[http://dx.doi.org/10.1016/j.dit.2013.05.010]
[http://dx.doi.org/10.1002/cbdv.200490173] [PMID: 17191918]
[http://dx.doi.org/10.1002/chin.201431276]
[http://dx.doi.org/10.2174/156802611795347645] [PMID: 21401501]
[http://dx.doi.org/10.1016/S0028-3908(99)00010-6] [PMID: 10462127]
[http://dx.doi.org/10.2174/092986708784872357] [PMID: 18673223]
[http://dx.doi.org/10.1016/S0091-3057(01)00746-8] [PMID: 11888546]
[http://dx.doi.org/10.1016/S0960-894X(00)80460-6]
[http://dx.doi.org/10.1016/S1734-1140(09)70132-X] [PMID: 19903999]
[http://dx.doi.org/10.2174/156802608785161420] [PMID: 18691131]
[http://dx.doi.org/10.2174/156802610790411036] [PMID: 20166958]
[http://dx.doi.org/10.1016/j.bmc.2010.05.051] [PMID: 20541425]
[http://dx.doi.org/10.3389/fphar.2015.00162] [PMID: 26300776]
[http://dx.doi.org/10.3390/ijms22052329] [PMID: 33652672]
[http://dx.doi.org/10.1016/j.ejmech.2019.111690] [PMID: 31526973]
[http://dx.doi.org/10.1016/j.ejmech.2019.07.027] [PMID: 31325785]
[http://dx.doi.org/10.1016/j.ejmech.2015.05.003] [PMID: 26043160]
[http://dx.doi.org/10.1016/j.ejmech.2014.10.069] [PMID: 25461308]
[PMID: 11734617]
[http://dx.doi.org/10.3390/ijms15022024] [PMID: 24477263]
[http://dx.doi.org/10.1254/jphs.FP0040359] [PMID: 15351792]
[http://dx.doi.org/10.1016/j.bbr.2008.06.035] [PMID: 18657577]
[http://dx.doi.org/10.1038/nrd1983] [PMID: 16518376]
[http://dx.doi.org/10.1016/j.yebeh.2020.107034] [PMID: 32208337]
[http://dx.doi.org/10.1089/caff.2019.0022] [PMID: 32566903]
[http://dx.doi.org/10.1016/S0165-0173(00)00033-3] [PMID: 11011069]
[http://dx.doi.org/10.1021/jm00081a001] [PMID: 1738138]
[http://dx.doi.org/10.2174/0929867003374101] [PMID: 11032971]
[http://dx.doi.org/10.1016/j.lfs.2011.05.011] [PMID: 21684291]
[http://dx.doi.org/10.3390/ph14070657] [PMID: 34358083]
[http://dx.doi.org/10.3390/ph13080161] [PMID: 32722122]
[http://dx.doi.org/10.1080/14756366.2016.1247060] [PMID: 28114825]
[http://dx.doi.org/10.1021/acschemneuro.6b00218] [PMID: 27569066]
[http://dx.doi.org/10.1021/acs.jmedchem.6b01068] [PMID: 27933962]
[http://dx.doi.org/10.1016/j.bmc.2016.04.048] [PMID: 27161878]
[http://dx.doi.org/10.1097/00004691-200302000-00005] [PMID: 12684557]
[http://dx.doi.org/10.1016/B978-0-444-53630-3.00008-7] [PMID: 21094889]
[http://dx.doi.org/10.1016/j.ejmech.2019.111824] [PMID: 31708184]
[http://dx.doi.org/10.1016/j.bioorg.2017.12.031] [PMID: 29331765]
[http://dx.doi.org/10.1016/j.bioorg.2017.07.017] [PMID: 28806600]
[http://dx.doi.org/10.1002/ardp.201700146] [PMID: 28758238]
[http://dx.doi.org/10.3390/molecules20046827] [PMID: 25884556]
[http://dx.doi.org/10.3109/14756366.2011.618129] [PMID: 21981001]
[http://dx.doi.org/10.2174/1874467207666140219122337] [PMID: 24720538]
[http://dx.doi.org/10.1021/acs.organomet.6b00575]
[http://dx.doi.org/10.1073/pnas.96.10.5780] [PMID: 10318961]
[http://dx.doi.org/10.2174/092986712801323207] [PMID: 22709008]
[http://dx.doi.org/10.1002/cmdc.201800541] [PMID: 30246417]
[http://dx.doi.org/10.1016/j.ejmech.2018.01.034] [PMID: 29360044]
[http://dx.doi.org/10.1016/j.ejmech.2016.02.032] [PMID: 26922225]
[http://dx.doi.org/10.1021/jm400182t] [PMID: 23697626]
[http://dx.doi.org/10.1152/physrev.00015.2008] [PMID: 19126755]
[http://dx.doi.org/10.1074/jbc.R112.407668] [PMID: 23038257]
[http://dx.doi.org/10.1016/j.tips.2014.12.002] [PMID: 25639674]
[http://dx.doi.org/10.1017/S0033583510000168] [PMID: 20849671]
[http://dx.doi.org/10.1124/pr.113.008581] [PMID: 26419447]
[http://dx.doi.org/10.1038/nrd2927] [PMID: 19721446]
[http://dx.doi.org/10.1016/0024-3205(92)90249-O] [PMID: 1740971]
[http://dx.doi.org/10.1146/annurev.neuro.22.1.443] [PMID: 10202545]
[http://dx.doi.org/10.1523/JNEUROSCI.6159-08.2009] [PMID: 19587288]
[http://dx.doi.org/10.1016/S0166-4328(00)00211-4] [PMID: 10942043]
[http://dx.doi.org/10.1093/ntr/nty116] [PMID: 30137524]
[http://dx.doi.org/10.1016/S0161-813X(02)00036-0] [PMID: 12428730]
[http://dx.doi.org/10.1124/mol.107.035998] [PMID: 17409284]
[http://dx.doi.org/10.1176/appi.ajp.2008.07071135] [PMID: 18381905]
[http://dx.doi.org/10.1016/j.bcp.2009.05.030] [PMID: 19482012]
[http://dx.doi.org/10.2174/1570159X15666170818102108] [PMID: 28820052]
[http://dx.doi.org/10.2174/138161206775474486] [PMID: 16472136]
[http://dx.doi.org/10.1016/j.neuropharm.2006.03.012] [PMID: 16678864]
[http://dx.doi.org/10.1016/j.neuropharm.2020.108108] [PMID: 32353365]
[http://dx.doi.org/10.1021/jacs.6b10746] [PMID: 28221788]
[PMID: 9647869]
[http://dx.doi.org/10.1146/annurev.pharmtox.44.101802.121622] [PMID: 14744253]
[http://dx.doi.org/10.1186/1471-2202-13-42] [PMID: 22540185]
[http://dx.doi.org/10.1038/sj.bjp.0705002] [PMID: 12522072]
[http://dx.doi.org/10.1016/0306-4522(91)90181-M] [PMID: 2052149]
[http://dx.doi.org/10.1002/cne.23323] [PMID: 23504804]
[http://dx.doi.org/10.1021/acschemneuro.8b00613] [PMID: 30547573]
[http://dx.doi.org/10.1016/j.crad.2010.03.011] [PMID: 20541650]
[http://dx.doi.org/10.1016/j.bmc.2019.07.036] [PMID: 31353076]
[http://dx.doi.org/10.1021/jm501065t] [PMID: 25279444]