Discovery of [(3-Phenylphenyl)carbamoylamino]benzenesulfonyl Fluoride (RTICBM-303), a Cannabinoid Receptor Type 1 Allosteric Modulator that Suppresses Cue- and Drug-Primed Methamphetamine Seeking in Rats.

The development of effective pharmacotherapies for methamphetamine (METH) use disorder remains a critical challenge, prompting interest in strategies to modulate the endocannabinoid system because of its involvement in reward regulation. We hereby report the identification and characterization of a negative allosteric modulator (NAM) of the CB1 receptor, RTICBM-303 (11), which displayed good potencies in several CB1 in vitro assays, concentration dependently reduced the Emax of the agonist CP55,940, and increased [3H]CP55,940 binding. Compound 11, bearing a 4-fluorosulfonyl substituent, demonstrated considerably improved metabolic stability in rat liver microsomes (T1/2 > 255 min), favorable brain penetration, but limited aqueous solubility. Finally, 11 (10 mg/kg, i.p.) significantly and selectively reduced both cue-induced and drug-primed reinstatement of METH-seeking behavior in rats, without altering operant responding for food. These findings support 11 for further preclinical development and highlight the broader therapeutic potential of CB1 NAMs for treating stimulant use disorders.