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.

中文翻译：

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作为大麻素1型受体变构调节剂的1-Phenyl-3-Thiophenylurea衍生物的合成和药理评价。

我们先前曾报道过二芳基脲衍生物是大麻素1型受体（CB1）变构调节剂，可有效减弱可卡因的寻找行为。在这里，我们扩展了PSNCBAM-1（2）在直接连接到脲部分的中心苯环上的构效关系。噻吩环取代导致11在钙动员，[35S]GTPγS结合和cAMP分析方面具有改进或相当的效力，而非芳香环取代则导致调节活性显着降低。这些化合物在[35S]GTPγS结合中没有反向激动作用，这一特征通常被认为会导致不良的精神病学效应。尽管11在大鼠肝微粒体中具有良好的代谢稳定性，但显示出适度的溶解度和血脑屏障通透性。