期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 63, 期 14, 页码 7529-7544出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.9b01953
关键词
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资金
- National Institutes of Health [R21 MH093844, R01 DA038446, K05 DA020087, P30 DA28821, T32 DA07287, F31 DA038922, DA038446-S1, F31 DA045511]
- M.D. Distinguished Chair Endowment Fund
- Center for Addiction Research at UTMB
- R.A. Welch Foundation Chemistry and Biology Collaborative Grant from Gulf Coast Consortia (GCC) for Chemical Genomics
- Keck Center for Interdisciplinary Bioscience Training of the GCC (NIGMS) [T32 GM089657-03]
- Sealy and Smith Foundation
- John Sealy Memorial Endowment Fund
- National Institute of Mental Health Psychoactive Drug Screening Program (PDSP) [HHSN271-2013-00017-C]
Targeting the serotonin (5-HT) 5-HT2C receptor (5-HT2CR) allosteric site to potentiate endogenous 5-HT tone may provide novel therapeutics to alleviate the impact of costly, chronic diseases such as obesity and substance use disorders. Expanding upon our recently described 5-HT2CR-positive allosteric modulators (PAMs) based on the 4-alkylpiperidine-2-carboxamide scaffold, we optimized the undecyl moiety at the 4-position with variations of cyclohexyl- or phenyl-containing fragments to reduce rotatable bonds and lipophilicity. Compound 12 (CTW0415) was discovered as a 5-HT2CR PAM with improved pharmacokinetics and reduced off-target interactions relative to our previous series of molecules. The in vivo efficacy of compound 12 to potentiate the effects of a selective 5-HT2CR agonist was established in a drug discrimination assay. Thus, 12 is reported as a 5-HT2CR PAM with characteristics suitable for in vivo pharmacological studies to further probe the biological and behavioral mechanisms of allosteric modulation of a receptor important in several chronic diseases.
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