1. Discovery of 4-Phenylpiperidine-2-Carboxamide Analogues as Serotonin 5-HT 2C Receptor-Positive Allosteric Modulators with Enhanced Drug-like Properties.
- Author
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Wold EA, Garcia EJ, Wild CT, Miszkiel JM, Soto CA, Chen J, Pazdrak K, Fox RG, Anastasio NC, Cunningham KA, and Zhou J
- Subjects
- Animals, Binding Sites, CHO Cells, Cricetulus, Drug Design, Molecular Docking Simulation, Molecular Structure, Piperidines chemical synthesis, Piperidines metabolism, Piperidines pharmacokinetics, Receptor, Serotonin, 5-HT2C chemistry, Serotonin 5-HT2 Receptor Agonists chemical synthesis, Serotonin 5-HT2 Receptor Agonists metabolism, Serotonin 5-HT2 Receptor Agonists pharmacokinetics, Structure-Activity Relationship, Piperidines pharmacology, Receptor, Serotonin, 5-HT2C metabolism, Serotonin 5-HT2 Receptor Agonists pharmacology
- Abstract
Targeting the serotonin (5-HT) 5-HT
2C receptor (5-HT2C 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-HT2C 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 12 (CTW0415) was discovered as a 5-HT2C R PAM with improved pharmacokinetics and reduced off-target interactions relative to our previous series of molecules. The in vivo efficacy of compound 12 to potentiate the effects of a selective 5-HT2C R agonist was established in a drug discrimination assay. Thus, 12 is reported as a 5-HT2C 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.- Published
- 2020
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