Center for Drug Discovery, RTI International, P.O. Box 12194, Research Triangle Park, NC 27709-2194, USA.
Molecules. 2022 Sep 2;27(17):5672. doi: 10.3390/molecules27175672.
Selective modulation of peripheral cannabinoid receptors (CBRs) has potential therapeutic applications in medical conditions, including obesity, diabetes, liver diseases, GI disorders and pain. While there have been considerable efforts to produce selective antagonists or full agonists of CBRs, there has been limited reports on the development of partial agonists. Partial agonists targeting peripheral CBRs may have desirable pharmacological profiles while not producing centrally mediated dissociative effects. Bayer reported that BAY 59-3074 is a CNS penetrant partial agonist of both CB1 and CB2 receptors with efficacy in rat models of neuropathic and inflammatory pain. In this report, we demonstrate our efforts to synthesize analogs that would favor peripheral selectivity, while maintaining partial agonism of CB1. Our efforts led to the identification of a novel compound, which is a partial agonist of the human CB1 (hCB1) receptor with vastly diminished brain exposure compared to BAY 59-3074.
外周大麻素受体（CBRs）的选择性调节在医学病症中具有潜在的治疗应用，包括肥胖、糖尿病、肝脏疾病、胃肠道疾病和疼痛。虽然已经做出了相当大的努力来生产 CBRs 的选择性拮抗剂或完全激动剂，但关于部分激动剂的开发却鲜有报道。针对外周 CBRs 的部分激动剂可能具有理想的药理学特性，而不会产生中枢介导的分离效应。拜耳公司报道称，BAY 59-3074 是一种中枢神经系统穿透性的 CB1 和 CB2 受体的部分激动剂，在神经病理性和炎症性疼痛的大鼠模型中具有疗效。在本报告中，我们展示了我们努力合成的类似物，这些类似物有利于外周选择性，同时保持 CB1 的部分激动作用。我们的努力确定了一种新型化合物，它是一种人 CB1（hCB1）受体的部分激动剂，与 BAY 59-3074 相比，其大脑暴露量大大减少。
