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Synthesis and pharmacological evaluation of 1-phenyl-3-thiophenylurea derivatives as cannabinoid type-1 receptor allosteric modulators
Nguyen, T., Gamage, T. F., Decker, A. M., Barrus, D., Langston, T. L., Li, J.-X., Thomas, B. F., & Zhang, Y. (2019). Synthesis and pharmacological evaluation of 1-phenyl-3-thiophenylurea derivatives as cannabinoid type-1 receptor allosteric modulators. Journal of Medicinal Chemistry, 62(21), 9806-9823. https://doi.org/10.1021/acs.jmedchem.9b01161
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.
