2. Academic Validation
  3. 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

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

  • J Med Chem. 2022 Jan 13;65(1):257-270. doi: 10.1021/acs.jmedchem.1c01432.
Thuy Nguyen 1,  Thomas F Gamage 1,  David B Finlay 2,  Ann M Decker 1,  Tiffany L Langston 1,  Daniel Barrus 1,  Michelle Glass 2,  Jun-Xu Li 3,  Terry P Kenakin 4,  Yanan Zhang 1
Affiliations

Affiliations

  • 1 Research Triangle Institute, Research Triangle Park, Research Triangle Park, North Carolina 27709, United States.
  • 2 Department of Pharmacology and Toxicology, School of Biomedical Sciences, University of Otago, Dunedin 9054, New Zealand.
  • 3 Department of Pharmacology and Toxicology, University at Buffalo, the State University of New York, Buffalo, New York 14214, United States.
  • 4 Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina 27599, United States.
PMID: 34929081 DOI: 10.1021/acs.jmedchem.1c01432
Abstract

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.

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