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


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.

SUBMITTER: Wild CT 

PROVIDER: S-EPMC6533912 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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

Wild Christopher T CT   Miszkiel Joanna M JM   Wold Eric A EA   Soto Claudia A CA   Ding Chunyong C   Hartley Rachel M RM   White Mark A MA   Anastasio Noelle C NC   Cunningham Kathryn A KA   Zhou Jia J  

Journal of medicinal chemistry 20180413 1


An impaired signaling capacity of the serotonin (5-HT) 5-HT<sub>2C</sub> receptor (5-HT<sub>2C</sub>R) has been implicated in the neurobehavioral processes that promote relapse vulnerability in cocaine use disorder (CUD). Restoration of the diminished 5-HT<sub>2C</sub>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  ...[more]

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