1. Academic Validation
  2. Synthesis and Pharmacological Evaluation of 1-Phenyl-3-Thiophenylurea Derivatives as Cannabinoid Type-1 Receptor Allosteric Modulators

Synthesis and Pharmacological Evaluation of 1-Phenyl-3-Thiophenylurea Derivatives as Cannabinoid Type-1 Receptor Allosteric Modulators

  • J Med Chem. 2019 Nov 14;62(21):9806-9823. doi: 10.1021/acs.jmedchem.9b01161.
Thuy Nguyen 1 Thomas F Gamage 1 Ann M Decker 1 Daniel Barrus 1 Tiffany L Langston 1 Jun-Xu Li 2 Brian F Thomas 1 Yanan Zhang 1
Affiliations

Affiliations

  • 1 Research Triangle Institute , Research Triangle Park , North Carolina 27709 , United States.
  • 2 Department of Pharmacology and Toxicology , University of Buffalo, the State University of New York , Buffalo , New York 14214 , United States.
Abstract

We previously reported diarylurea derivatives as cannabinoid type-1 receptor (CB1) allosteric modulators, which were effective in attenuating cocaine-seeking behavior. Herein, we extended the structure-activity relationships of PSNCBAM-1 (2) at the central phenyl ring directly connected to the urea moiety. Replacement with a thiophene ring led to 11 with improved or comparable potencies in calcium mobilization, [35S]GTPγS binding, and cAMP assays, whereas substitution with nonaromatic rings led to significant attenuation of the modulatory activity. These compounds had no inverse agonism in [35S]GTPγS binding, a characteristic that is often thought to contribute to adverse psychiatric effects. While 11 had good metabolic stability in rat liver microsomes, it showed modest solubility and blood-brain barrier permeability. Compound 11 showed an insignificant attenuation of cocaine seeking behavior in rats, most likely due to its limited CNS penetration, suggesting that pharmacokinetics and distribution play a role in translating the in vitro efficacy to in vivo behavior.

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