Specific tuning of cannabinoid 1 receptor (CB1R) activity by small-molecule allosteric modulators is a therapeutic modality with multiple properties inherently advantageous to therapeutic applications. We previously generated a library of unique CB1R positive allosteric modulators (PAMs) derived from GAT211, which has three pharmacophoric sites critical to its ago-PAM activity. To elaborate our CB1R PAM library, we report the rational design and molecular-pharmacology profiling of several 2-phenylindole analogs modified at the “site-III” aromatic ring. The comprehensive structure–activity relationship (SAR) investigation demonstrates that attaching small lipophilic functional groups on the ortho-position of the GAT211 site-III phenyl ring could markedly enhance CB1R ago-PAM activity. Select site-III modifications also improved GAT211’s water solubility. The SAR reported both extends the structural diversity of this compound class and demonstrates the utility of GAT211’s site-III for improving the parent compound’s drug-like properties of potency and/or aqueous solubility.

小分子变构调节剂对大麻素1受体（CB1R）活性的特定调节是一种具有多种特性的治疗方式，固有地对治疗应用有利。我们之前生成了一个来自GAT211的独特CB1R阳性变构调节剂（PAM）库，该库具有对其前PAM活性至关重要的三个药效学位点。为了阐述我们的CB1R PAM库，我们报告了在“位点III”芳环上修饰的几种2-苯基吲哚类似物的合理设计和分子药理学分析。全面的结构-活性关系（SAR）研究表明，在邻位上附着小的亲脂性官能团GAT211位点-III苯环的-位置可以显着增强CB1R前-PAM活性。选择的III位修饰也改善了GAT211的水溶性。SAR报告既扩展了这类化合物的结构多样性，又证明了GAT211位点III在改善母体化合物的药效和/或水溶性方面的效用。