Bosier Barbara, Hermans Emmanuel
Unité de Chimie Pharmaceutique et de Radiopharmacie (UCL 7340), Université Catholique de Louvain, B-1200 Brussels, Belgium.
Trends Pharmacol Sci. 2007 Aug;28(8):438-46. doi: 10.1016/j.tips.2007.06.001. Epub 2007 Jul 13.
Most drugs acting on G-protein-coupled receptors (GPCRs) are classically defined as agonists, partial agonists or antagonists. This simplified classification seems sufficient to explain most of their therapeutic properties. The more recent description of inverse agonism has helped to revise theoretical models of GPCR function, but the therapeutic implications of the new concepts remain clearly restricted. Further complexity has arisen with demonstrations that a given receptor can adopt various conformations that support coupling with distinct G proteins. Because the related signaling pathways seem to be differentially affected by some ligands, the concept of 'functional selectivity' has been proposed, calling for a revision of the definitions of agonism and intrinsic efficacy. Evidence of complexity in G-protein coupling and examples of functional selectivity are accumulating, opening perspectives for drug development. Although such complexity should be regarded as an opportunity to gain pharmacological specificity, unraveling the physiological implications of these concepts is essential before their therapeutic relevance can be defined.
大多数作用于G蛋白偶联受体（GPCRs）的药物传统上被定义为激动剂、部分激动剂或拮抗剂。这种简化的分类似乎足以解释它们的大多数治疗特性。反向激动作用的最新描述有助于修正GPCR功能的理论模型，但这些新概念的治疗意义显然仍然有限。随着有证据表明给定的受体可以采用多种构象以支持与不同的G蛋白偶联，情况变得更加复杂。由于相关的信号通路似乎受到某些配体的不同影响，因此提出了“功能选择性”的概念，这就需要对激动作用和内在效力的定义进行修订。G蛋白偶联复杂性的证据和功能选择性的例子不断积累，为药物开发开辟了前景。尽管这种复杂性应被视为获得药理学特异性的机会，但在确定这些概念的治疗相关性之前，阐明其生理意义至关重要。
