PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, An der Immenburg 4, D-53121 Bonn, Germany.
Pharmacol Ther. 2012 Sep;135(3):292-315. doi: 10.1016/j.pharmthera.2012.06.002. Epub 2012 Jun 19.
Rhodopsin-like (class A) G protein-coupled receptors (GPCRs) are one of the most important classes of drug targets. The discovery that these GPCRs can be allosterically modulated by small drug molecules has opened up new opportunities in drug development. It will allow the drugability of "difficult targets", such as GPCRs activated by large (glyco)proteins, or by very polar or highly lipophilic physiological agonists. Receptor subtype selectivity should be more easily achievable with allosteric than with orthosteric ligands. Allosteric modulation will allow a broad spectrum of pharmacological effects largely expanding that of orthosteric ligands. Furthermore, allosteric modulators may show an improved safety profile as compared to orthosteric ligands. Only recently, the explicit search for allosteric modulators has been started for only a few rhodopsin-like GPCRs. The first negative allosteric modulators (allosteric antagonists) of chemokine receptors, maraviroc (CCR5 receptor), used in HIV therapy, and plerixafor (CXCR4 receptor) for stem cell mobilization, have been approved as drugs. The development of allosteric modulators for rhodopsin-like GPCRs as novel drugs is still at an early stage; it appears highly promising.
视紫红质样（A 类）G 蛋白偶联受体（GPCRs）是最重要的药物靶点之一。这些 GPCR 可以被小分子药物变构调节的发现，为药物开发开辟了新的机会。它将使“难靶”（如由大（糖）蛋白或非常极性或高度亲脂性生理激动剂激活的 GPCR）的药物化成为可能。与变构配体相比，变构调节剂应该更容易实现受体亚型选择性。变构调节将允许广泛的药理学效应，在很大程度上扩大了变构配体的效应。此外，与变构配体相比，变构调节剂可能具有改善的安全性。直到最近，才开始针对少数视紫红质样 GPCR 进行明确的变构调节剂搜索。第一批用于 HIV 治疗的趋化因子受体的负变构调节剂（变构拮抗剂），如马拉维若（CCR5 受体）和用于干细胞动员的plerixafor（CXCR4 受体），已被批准为药物。作为新型药物，视紫红质样 GPCR 变构调节剂的开发仍处于早期阶段；它似乎非常有前途。
