Development of 3‑(4-Chlorophenyl)-1-(phenethyl)urea Analogues as Allosteric Modulators of the Cannabinoid Type‑1 Receptor: RTICBM-189 is Brain Penetrant and Attenuates Reinstatement of Cocaine-Seeking Behavior

We have shown that CB1 receptor negative allosteric modulators (NAMs) attenuated the reinstatement of cocaine-seeking behaviors in rats. In an effort to further define the structure–activity relationships and assess the druglike properties of the 3-(4-chlorophenyl)-1-(phenethyl)­urea-based CB1 NAMs that we recently reported, we introduced substituents of different electronic properties and sizes to the phenethyl group and evaluated their potency in CB1 calcium mobilization, cAMP, and GTPγS assays. We found that 3-position substitutions such as Cl, F, and Me afforded enhanced CB1 potency, whereas 4-position analogues were generally less potent. The 3-chloro analogue (31, RTICBM-189) showed no activity at >50 protein targets and excellent brain permeation but relatively low metabolic stability in rat liver microsomes. Pharmacokinetic studies in rats confirmed the excellent brain exposure of 31 with a brain/plasma ratio Kp of 2.0. Importantly, intraperitoneal administration of 31 significantly and selectively attenuated the reinstatement of the cocaine-seeking behavior in rats without affecting locomotion.