Discovery of 4-Phenylpiperidine-2-Carboxamide Analogues as Serotonin 5-HT 2C Receptor-Positive Allosteric Modulators with Enhanced Drug-like Properties

Targeting the serotonin (5-HT) 5-HT receptor (5-HT R) allosteric site to potentiate endogenous 5-HT tone may provide novel therapeutics to alleviate the impact of costly, chronic diseases such as obesity and substance use disorders. Expanding upon our recently described 5-HT R-positive allosteric mo...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2020-07, Vol.63 (14), p.7529-7544
Main Authors: Wold, Eric A, Garcia, Erik J, Wild, Christopher T, Miszkiel, Joanna M, Soto, Claudia A, Chen, Jianping, Pazdrak, Konrad, Fox, Robert G, Anastasio, Noelle C, Cunningham, Kathryn A, Zhou, Jia
Format: Article
Language:English
Subjects:
Animals
Binding Sites
CHO Cells
Cricetulus
Drug Design
Molecular Docking Simulation
Molecular Structure
Piperidines - chemical synthesis
Piperidines - metabolism
Piperidines - pharmacokinetics
Piperidines - pharmacology
Receptor, Serotonin, 5-HT2C - chemistry
Receptor, Serotonin, 5-HT2C - metabolism
Serotonin 5-HT2 Receptor Agonists - chemical synthesis
Serotonin 5-HT2 Receptor Agonists - metabolism
Serotonin 5-HT2 Receptor Agonists - pharmacokinetics
Serotonin 5-HT2 Receptor Agonists - pharmacology
Structure-Activity Relationship
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Summary:Targeting the serotonin (5-HT) 5-HT receptor (5-HT R) allosteric site to potentiate endogenous 5-HT tone may provide novel therapeutics to alleviate the impact of costly, chronic diseases such as obesity and substance use disorders. Expanding upon our recently described 5-HT R-positive allosteric modulators (PAMs) based on the 4-alkylpiperidine-2-carboxamide scaffold, we optimized the undecyl moiety at the 4-position with variations of cyclohexyl- or phenyl-containing fragments to reduce rotatable bonds and lipophilicity. Compound (CTW0415) was discovered as a 5-HT R PAM with improved pharmacokinetics and reduced off-target interactions relative to our previous series of molecules. The in vivo efficacy of compound to potentiate the effects of a selective 5-HT R agonist was established in a drug discrimination assay. Thus, is reported as a 5-HT R PAM with characteristics suitable for in vivo pharmacological studies to further probe the biological and behavioral mechanisms of allosteric modulation of a receptor important in several chronic diseases.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.9b01953