Design, Synthesis, and Characterization of 4-Undecylpiperidine-2-carboxamides as Positive Allosteric Modulators of the Serotonin (5-HT) 5-HT2C Receptor

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

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Abstract

An impaired signaling capacity of the serotonin (5-HT) 5-HT2C receptor (5-HT2CR) has been implicated in the neurobehavioral processes that promote relapse vulnerability in cocaine use disorder (CUD). Restoration of the diminished 5-HT2CR 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-HT2CR positive allosteric modulators (PAMs). Compound 16 (CYD-1-79) potentiated 5-HT-evoked intracellular calcium release in cells stably expressing the human 5-HT2CR but not the 5-HT2AR cells. A topographically distinct allosteric site was identified based on the newly solved 5-HT2CR structure. Compound 16 modulated 5-HT2CR-mediated spontaneous ambulation, partially substituted for the training dose of the 5-HT2CR 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

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ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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