Department of Pharmaceutical Sciences, Bouvé College of Health Sciences, Northeastern University, Boston, Massachusetts 02115, United States.
Center for Substance Abuse Research, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania 19140, United States.
J Med Chem. 2021 Jun 24;64(12):8104-8126. doi: 10.1021/acs.jmedchem.1c00040. Epub 2021 Apr 7.
We apply the magic methyl effect to improve the potency/efficacy of GAT211, the prototypic 2-phenylindole-based cannabinoid type-1 receptor (CB1R) agonist-positive allosteric modulator (ago-PAM). Introducing a methyl group at the α-position of nitro group generated two diastereomers, the greater potency and efficacy of , (±)- vs , (±)- constitutes the first demonstration of diastereoselective CB1R-allosteric modulator interaction. Of the (±)- enantiomers, (-)-(,)- evidenced improved potency over GAT211 as a CB1R ago-PAM, whereas (+)-(,)- was a CB1R allosteric agonist biased toward G protein- vs β-arrestin1/2-dependent signaling. (-)-(,)- and (+)-(,)- were devoid of undesirable side effects (triad test), and (+)-(,)- reduced intraocular pressure with an unprecedentedly long duration of action in a murine glaucoma model. (-)-(,)- docked into both a CB1R extracellular PAM and intracellular allosteric-agonist site(s), whereas (+)-(,)- preferentially engaged only the latter. Exploiting G-protein biased CB1R-allosteric modulation can offer safer therapeutic candidates for glaucoma and, potentially, other diseases.
我们应用神奇的甲基效应来提高 GAT211 的效力/功效，GAT211 是一种典型的 2-苯基吲哚类大麻素 1 型受体 (CB1R) 激动剂正变构调节剂 (ago-PAM)。在硝基的α位引入一个甲基生成了两个非对映异构体，(±)-与 (±)-的更高效力和功效构成了首次展示的 CB1R 变构调节剂相互作用的立体选择性。在(±)-对映异构体中，(-)-(,)-作为 CB1R ago-PAM 的效力优于 GAT211，而 (+)-(,)-则是偏向于 G 蛋白与β-arrestin1/2 依赖性信号的 CB1R 变构激动剂。(-)-(,)-和 (+)-(,)-均没有不良副作用（三联测试），并且 (+)-(,)-在小鼠青光眼模型中具有前所未有的长作用持续时间降低了眼内压。(-)-(,)-同时结合到 CB1R 细胞外 PAM 和细胞内变构激动剂位点，而 (+)-(,)-则优先仅结合后者。利用 G 蛋白偏向的 CB1R 变构调节可以为青光眼和潜在的其他疾病提供更安全的治疗候选物。
