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.