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
التفاصيل البيبلوغرافية
العنوان:
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 CB(1) 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 drug-like properties of the 3-(4-chlorophenyl)-1-(phenethyl)urea-based CB(1) NAMs that we recently reported, we introduced substituents of different electronic properties and size to the phenethyl group and evaluated their potency in CB(1) calcium mobilization, cAMP and GTPγS assays. We found that 3-position substitutions such as Cl, F, Me afforded enhanced CB(1) potency, whereas 4-position analogs were generally less potent. The 3-chloro analog (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 cocaine-seeking behavior in rats without affecting locomotion.
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