TY - JOUR
T1 - Design, Synthesis, and Characterization of 4-Undecylpiperidine-2-carboxamides as Positive Allosteric Modulators of the Serotonin (5-HT) 5-HT 2C Receptor
AU - Wild, Christopher T.
AU - Miszkiel, Joanna M.
AU - Wold, Eric A.
AU - Soto, Claudia A.
AU - Ding, Chunyong
AU - Hartley, Rachel
AU - White, Mark A.
AU - Anastasio, Noelle C.
AU - Cunningham, Kathryn A.
AU - Zhou, Jia
N1 - Publisher Copyright:
© 2018 American Chemical Society.
PY - 2019/10/1
Y1 - 2019/10/1
N2 - 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.
AB - 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.
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U2 - 10.1021/acs.jmedchem.8b00401
DO - 10.1021/acs.jmedchem.8b00401
M3 - Article
C2 - 29620897
AN - SCOPUS:85059508564
SN - 0022-2623
VL - 62
SP - 288
EP - 305
JO - Journal of medicinal chemistry
JF - Journal of medicinal chemistry
IS - 1
ER -