Design, Synthesis, and Characterization of 4-Undecylpiperidine-2-carboxamides as Positive Allosteric Modulators of the Serotonin (5-HT) 5-HT 2C Receptor

Christopher T. Wild, Joanna M. Miszkiel, Eric A. Wold, Claudia A. Soto, Chunyong Ding, Rachel M. Hartley, Mark A. White, Noelle C. Anastasio, Kathryn A. Cunningham, Jia Zhou

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

An impaired signaling capacity of the serotonin (5-HT) 5-HT 2C receptor (5-HT 2C R) has been implicated in the neurobehavioral processes that promote relapse vulnerability in cocaine use disorder (CUD). Restoration of the diminished 5-HT 2C R signaling through positive allosteric modulation presents a novel therapeutic approach. Several new molecules with the 4-alkylpiperidine-2-carboxamide scaffold were designed, synthesized, and pharmacologically evaluated, leading to the discovery of selective 5-HT 2C R positive allosteric modulators (PAMs). Compound 16 (CYD-1-79) potentiated 5-HT-evoked intracellular calcium release in cells stably expressing the human 5-HT 2C R but not the 5-HT 2A R cells. A topographically distinct allosteric site was identified based on the newly solved 5-HT 2C R structure. Compound 16 modulated 5-HT 2C R-mediated spontaneous ambulation, partially substituted for the training dose of the 5-HT 2C R agonist WAY163909, synergized with a low dose of WAY163909 to substitute fully for the stimulus effects of WAY163909, and attenuated relapse vulnerability as assessed in a rodent self-administration model, indicating its therapeutic promise for CUD.

Original languageEnglish (US)
Pages (from-to)288-305
Number of pages18
JournalJournal of medicinal chemistry
Volume62
Issue number1
DOIs
StatePublished - Oct 1 2019

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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