Research Triangle Institute, Research Triangle Park, NC 27709, USA.
Department of Pharmacology and Toxicology, University of Otago, Dunedin 9054, New Zealand.
Bioorg Med Chem. 2021 Jul 1;41:116215. doi: 10.1016/j.bmc.2021.116215. Epub 2021 May 12.
Allosteric modulation offers an alternate approach to target the cannabinoid type-1 receptor (CB) for therapeutic benefits. Examination of the two widely studied prototypic CB negative allosteric modulators (NAMs) Org27569 and PSNCBAM-1 revealed structural resemblance and similar structure-activity relationships (SARs). In silico docking and dynamics simulation studies using the crystal structure of CB co-bound with CP55,940 and Org27569 suggested that Org27569 and PSNCBAM-1 occupied the same binding pocket and several common interactions were present in both series with the CB receptor. A new scaffold was therefore designed by merging the key structural features from the two series and the hybrids retained these binding features in the in silico docking studies. In addition, one such hybrid displayed similar functions to Org27569 in dynamic simulations by preserving a key R214-D338 salt bridge and maintaining an antagonist-like Helix3-Helix6 interhelical distance. Based on these results, a series of hybrids were synthesized and assessed in calcium mobilization, [S]GTPγS binding and cAMP assays. Several compounds displayed comparable potencies to Org27569 and PSNCBAM-1 in these assays. This work offers new insight of the SAR requirement at the allosteric site of the CB receptor and provides a new scaffold that can be optimized for the development of future CB allosteric modulators.
变构调节为靶向大麻素受体 1（CB1）以获得治疗益处提供了一种替代方法。对两种广泛研究的典型 CB 负变构调节剂（NAM）Org27569 和 PSNCBAM-1 的研究表明，它们具有结构相似性和相似的构效关系（SAR）。使用 CB 与 CP55,940 和 Org27569 共结合的晶体结构进行的计算机对接和动力学模拟研究表明，Org27569 和 PSNCBAM-1 占据了相同的结合口袋，并且两个系列中都存在几个共同的相互作用与 CB 受体。因此，通过合并两个系列的关键结构特征设计了一个新的支架，并且在计算机对接研究中，杂种保留了这些结合特征。此外，在动态模拟中，其中一个杂种通过保留关键的 R214-D338 盐桥并保持类似拮抗剂的 Helix3-Helix6 螺旋间距离，显示出与 Org27569 相似的功能。基于这些结果，合成了一系列杂种并在钙动员、[S]GTPγS 结合和 cAMP 测定中进行了评估。在这些测定中，几种化合物的效力与 Org27569 和 PSNCBAM-1 相当。这项工作为 CB 受体变构位点的 SAR 要求提供了新的见解，并提供了一个新的支架，可用于开发未来的 CB 变构调节剂。
