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

• Published in: Journal of medicinal chemistry Vol. 62; no. 1; pp. 288 - 305
• Main Authors: Wild, Christopher T, Miszkiel, Joanna M, Wold, Eric A, Soto, Claudia A, Ding, Chunyong, Hartley, Rachel M, White, Mark A, Anastasio, Noelle C, Cunningham, Kathryn A, Zhou, Jia
• Format: Journal Article
• Language: English
• Published: United States 10-01-2019
• Subjects: Allosteric Regulation; Allosteric Site; Amides - chemical synthesis; Amides - chemistry; Amides - pharmacokinetics; Amides - pharmacology; Animals; Azepines - chemistry; Calcium - metabolism; CHO Cells; 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
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.8b00401

An impaired signaling capacity of the serotonin (5-HT) 5-HT
receptor (5-HT
R) has been implicated in the neurobehavioral processes that promote relapse vulnerability in cocaine use disorder (CUD). Restoration of the diminished 5-HT
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
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
R but not the 5-HT
R cells. A topographically distinct allosteric site was identified based on the newly solved 5-HT
R structure. Compound 16 modulated 5-HT
R-mediated spontaneous ambulation, partially substituted for the training dose of the 5-HT
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.