Brown Katie M, Roy Kuldeep K, Hockerman Gregory H, Doerksen Robert J, Colby David A
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University , West Lafayette, Indiana 47907, United States.
Department of Biomolecular Sciences, University of Mississippi , University, Mississippi 38677, United States.
J Med Chem. 2015 Aug 27;58(16):6336-47. doi: 10.1021/jm5018913. Epub 2015 Apr 24.
Since the discovery of the GABA(B) agonist and muscle relaxant baclofen, there have been substantial advancements in the development of compounds that activate the GABA(B) receptor as agonists or positive allosteric modulators. For the agonists, most of the existing structure-activity data apply to understanding the role of substituents on the backbone of GABA as well as replacing the carboxylic acid and amine groups. In the cases of the positive allosteric modulators, the allosteric binding site(s) and structure-activity relationships are less well-defined; however, multiple classes of molecules have been discovered. The recent report of the X-ray structure of the GABA(B) receptor with bound agonists and antagonists provides new insights for the development of compounds that bind the orthosteric site of this receptor. From a therapeutic perspective, these data have enabled efforts in drug discovery in areas of addiction-related behavior, the treatment of anxiety, and the control of muscle contractility.
自从发现γ-氨基丁酸B（GABA(B)）激动剂和肌肉松弛剂巴氯芬以来，在开发作为激动剂或正变构调节剂激活GABA(B)受体的化合物方面取得了重大进展。对于激动剂而言，大多数现有的构效关系数据适用于理解GABA主链上取代基的作用以及取代羧酸和胺基。在正变构调节剂的情况下，变构结合位点和构效关系的定义不太明确；然而，已经发现了多类分子。最近关于结合激动剂和拮抗剂的GABA(B)受体的X射线结构报告为开发结合该受体正位位点的化合物提供了新的见解。从治疗角度来看，这些数据推动了在成瘾相关行为、焦虑症治疗和肌肉收缩控制等领域的药物研发工作。
