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

J Med Chem. 2019 Jan 10;62(1):288-305. doi: 10.1021/acs.jmedchem.8b00401. Epub 2018 Apr 13.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation
  • Allosteric Site
  • Amides / chemical synthesis
  • Amides / chemistry*
  • Amides / pharmacokinetics
  • Amides / pharmacology
  • Animals
  • Azepines / chemistry
  • CHO Cells
  • Calcium / metabolism
  • Cricetinae
  • Cricetulus
  • Drug Design*
  • Half-Life
  • Indoles / chemistry
  • Locomotion / drug effects
  • Molecular Docking Simulation
  • Piperidines / chemistry
  • Protein Isoforms / chemistry
  • Protein Isoforms / metabolism
  • Protein Structure, Tertiary
  • Rats
  • Receptor, Serotonin, 5-HT2C / chemistry*
  • Receptor, Serotonin, 5-HT2C / genetics
  • Receptor, Serotonin, 5-HT2C / metabolism
  • Serotonin 5-HT2 Receptor Agonists / chemistry
  • Structure-Activity Relationship

Substances

  • 1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta(b)(1,4)diazepino(6,7,1hj)indole
  • Amides
  • Azepines
  • Indoles
  • Piperidines
  • Protein Isoforms
  • Receptor, Serotonin, 5-HT2C
  • Serotonin 5-HT2 Receptor Agonists
  • piperidine
  • Calcium