Targeting the serotonin (5-HT) 5-HT<sub>2C</sub> receptor (5-HT<sub>2C</sub>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<sub>2C</sub>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 <b>12</b> (CTW0415) was discovered as a 5-HT<sub>2C</sub>R PAM with improved pharmacokinetics and reduced off-target interactions relative to our previous series of molecules. The in vivo efficacy of compound <b>12</b> to potentiate the effects of a selective 5-HT<sub>2C</sub>R agonist was established in a drug discrimination assay. Thus, <b>12</b> is reported as a 5-HT<sub>2C</sub>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.