Department of Physiology, Graduate School of Pharmaceutical Sciences, Kyushu University.
Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University-Seoul.
Biol Pharm Bull. 2022;45(6):669-674. doi: 10.1248/bpb.b22-00143.
Agonists are defined as the ligands that activate intracellular signaling and evoke cellular responses. Synthetic and endogenous agonists should bind specific amino acids to activate G protein-coupled receptor (GPCR). Agonists that induce maximal responses are full agonists. Partial agonists cannot induce full responses unlike full agonists. In definition, antagonists inhibit agonist-stimulated responses by binding to orthosteric or allosteric sites. Antagonists modulate agonist-induced responses and are often related with inverse agonist activity. However, the relationship between antagonists and partial agonists is complex. An antagonist behaves as a partial agonist when the constitutive activity of the GPCR is high. In contrast, a partial agonist with very weak intrinsic activity may be classified as an antagonist. Thus, antagonisms of the compounds are influenced by constitutive activity of GPCRs, intrinsic activity and differences in the binding sites of GPCRs. Since "antagonism" has been revealed to have multiple aspects and more complex than previously thought, it may be difficult to classify each compound as simply "agonist" or "antagonist" as before. In this review, we discuss the recent findings and perspectives on the pharmacology of GPCR-binding antagonists, inverse agonists, and signaling.
激动剂被定义为激活细胞内信号转导并引起细胞反应的配体。合成和内源性激动剂应结合特定的氨基酸来激活 G 蛋白偶联受体（GPCR）。诱导最大反应的激动剂是完全激动剂。与完全激动剂不同，部分激动剂不能诱导完全反应。在定义上，拮抗剂通过与正位或变构结合位点结合来抑制激动剂刺激的反应。拮抗剂调节激动剂诱导的反应，通常与反向激动剂活性有关。然而，拮抗剂和部分激动剂之间的关系很复杂。当 GPCR 的组成活性较高时，拮抗剂表现为部分激动剂。相反，具有非常弱内在活性的部分激动剂可能被归类为拮抗剂。因此，化合物的拮抗作用受 GPCR 组成活性、内在活性和 GPCR 结合位点差异的影响。由于“拮抗作用”已经被揭示出具有多个方面，比以前想象的更为复杂，因此可能很难像以前那样简单地将每种化合物归类为“激动剂”或“拮抗剂”。在这篇综述中，我们讨论了关于 GPCR 结合拮抗剂、反向激动剂和信号转导的药理学的最新发现和观点。
