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 K_p of 2.0. Importantly, intraperitoneal administration of 31 significantly and selectively attenuated the reinstatement of the cocaine-seeking behavior in rats without affecting locomotion.