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Overdose deaths remain high for opioid use disorder, emphasizing the need to pursue innovative therapeutics. Classic psychedelic drugs that engage many monoamine receptors mitigate opioid use. Here, we tested the hypothesis that the preferential serotonin 5-HT 2A R agonist, 2,5-dimethoxy-4-iodoamphetamine (DOI) could reduce the demand for fentanyl in a preclinical model of fentanyl self-administration. Male and female Sprague-Dawley rats (n = 25–29) were implanted with indwelling jugular catheters and allowed to self-administer fentanyl (3.2 μg/kg/infusion). Rats progressed to a novel low price twice within-session threshold procedure where rats sampled the lowest price twice before decreasing the dose of fentanyl by a ¼ log every 10 minutes across 11 doses. Once stable, rats were pretreated with saline or DOI (0.01, 0.03, 1 mg/kg). Fentanyl consumption was analyzed using an exponentiated demand function to extract the dependent variables, Q 0 and α. Male and female rats acquired fentanyl self-administration in the lowest price twice within-session threshold procedure. DOI dose-dependently altered fentanyl intake such that 5-HT 2A R activation decreased Q 0 in female rats but increased Q 0 in male rats. For demand elasticity, DOI increased α in male rats but did not alter α in female rats. DOI did not alter inactive lever presses or latency. DOI reduces consumption at minimally constrained costs but did not affect the reinforcement value of fentanyl in female rats. Alternatively, DOI significantly reduced the reinforcement value of fentanyl in male rats. Biological sex alters the therapeutic efficacy of DOI and 5-HT 2A R activation sex-dependently alters opioid reinforcement. • Male and female Sprague-Dawley rats readily acquire fentanyl self-administration. • A modified low price twice within-session threshold procedure characterized fentanyl demand in male and female rats. • The 5-HT2A receptor agonist, 2,5-dimethoxy-4-iodoamphetamine (DOI) dose-dependently decreased demand intensity in female rats. • DOI dose-dependently increased demand elasticity in male rats but not female rats. • DOI reduced the reinforcing value of fentanyl in male but not female rats. [ABSTRACT FROM AUTHOR]

The serotonin 5-HT 2A receptor (5-HT 2A R) and 5-HT 2C R localize to the brain and share overlapping signal transduction facets that contribute to their roles in cognition, mood, learning, and memory. Achieving selective targeting of these receptors is challenged by the similarity in their 5-HT orthosteric binding pockets. A fragment-based discovery approach was employed to design and synthesize novel oleamide analogues as selective 5-HT 2C R or dual 5-HT 2C R/5-HT 2A R positive allosteric modulators (PAMs). Compound 13 ( JPC0323 ) exhibited on-target properties, acceptable plasma exposure and brain penetration, as well as negligible displacement to orthosteric sites of ∼50 GPCRs and transporters. Furthermore, compound 13 suppressed novelty-induced locomotor activity in a 5-HT 2C R-dependent manner, suggesting 5-HT 2C R PAM, but not 5-HT 2A R, activity at the level of the whole organism at the employed doses of 13 . We discovered new selective 5-HT 2C R PAMs and first-in-class 5-HT 2C R/5-HT 2A R dual PAMs that broaden the pharmacological toolbox to explore the biology of these vital receptors.

Targeting the serotonin (5-HT) 5-HT 2C receptor (5-HT 2C 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 2C 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-HT 2C 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-HT 2C R agonist was established in a drug discrimination assay. Thus, 12 is reported as a 5-HT 2C 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.