Discovery of 4-Phenylpiperidine-2-Carboxamide Analogues as Serotonin 5-HT2C Receptor-Positive Allosteric Modulators with Enhanced Drug-like Properties

Eric A. Wold, Erik J. Garcia, Christopher T. Wild, Joanna M. Miszkiel, Claudia A. Soto, Jianping Chen, Konrad Pazdrak, Robert G. Fox, Noelle C. Anastasio, Kathryn A. Cunningham, Jia Zhou

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)7529-7544
Number of pages16
JournalJournal of medicinal chemistry
Volume63
Issue number14
DOIs
StatePublished - Jul 23 2020

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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