Ong Jennifer, Kerr David I B
Department of Anaesthesia and Intensive Care, The University of Adelaide, Australia.
CNS Drug Rev. 2005 Autumn;11(3):317-34. doi: 10.1111/j.1527-3458.2005.tb00049.x.
Metabotropic gamma-aminobutyric acid(B) (GABAB) receptors for the major inhibitory transmitter GABA, together with metabotropic glutamate (mGLuRs) receptors, the extracellular calcium-sensing receptors (CaSRs), some V2R pheromone receptors and T1R taste receptors, belong to the family of 3 G-protein-coupled receptors (GPCRs). GABAB receptors are known to control neuronal excitability and modulate synaptic neurotransmission, playing a very important role in many physiological activities. These receptors are widely expressed and distributed in the nervous system and have been implicated in a variety of neurodegenerative and pathophysiological disorders including epilepsy, spasticity, chronic pain, depression, schizophrenia and drug addiction. To form a functional receptor entity, GABAB receptors must exist as a heterodimer consisting of GABAB1 and GABAB2 receptor subtypes with two 7-transmembrane proteins, and these subunits arise from distinct genes. The GABAB1 subunit binds the endogenous ligand within its extracellular N-terminus, whilst the GABAB2 subunit is not only essential for the correct trafficking of the GABAB1 subunit to the cell surface, but is also responsible for the interaction of the receptor with its cognate G-protein. Allosteric modulation has recently been recognized as an alternative pharmacological approach to gain selectivity in drug action. It is now generally accepted that modulators acting at the allosteric sites provide a novel perspective for the development of subtype-selective agents acting at GPCRs. These agents interact with allosteric binding sites quite separate from the highly conserved agonist binding region. In this review, we present a new class of phenylalkylamines, based on the lead compound fendiline, that are potent positive potentiators of GABAB receptor-mediated function and discuss their putative clinical applications. It is proposed that these new modulators may have therapeutic value in GABAB receptor pharmacology and are capable of selectively modifying GABAB receptor function. The allosteric modulators are offering an attractive and novel means to identify new leads, that are devoid of side effects associated with GABAB receptor agonists, and may, therefore, represent a major advance in the drug discovery process.
代谢型γ-氨基丁酸(B)（GABAB）受体作为主要抑制性神经递质γ-氨基丁酸（GABA）的受体，与代谢型谷氨酸（mGLuRs）受体、细胞外钙敏感受体（CaSRs）、一些V2R信息素受体和T1R味觉受体一起，属于三聚体G蛋白偶联受体（GPCRs）家族。已知GABAB受体可控制神经元兴奋性并调节突触神经传递，在许多生理活动中发挥着非常重要的作用。这些受体在神经系统中广泛表达和分布，并与多种神经退行性和病理生理疾病有关，包括癫痫、痉挛、慢性疼痛、抑郁症、精神分裂症和药物成瘾。为了形成功能性受体实体，GABAB受体必须以由GABAB1和GABAB2受体亚型组成的异二聚体形式存在，这两个亚型均为7次跨膜蛋白，且这些亚基来自不同的基因。GABAB1亚基在其细胞外N末端结合内源性配体，而GABAB2亚基不仅对于GABAB1亚基正确转运至细胞表面至关重要，而且还负责受体与其同源G蛋白的相互作用。变构调节最近已被认为是在药物作用中获得选择性的另一种药理学方法。现在人们普遍认为，作用于变构位点的调节剂为开发作用于GPCRs的亚型选择性药物提供了新的视角。这些药物与变构结合位点相互作用，该位点与高度保守的激动剂结合区域完全分开。在本综述中，我们基于先导化合物芬地林提出了一类新型苯烷基胺，它们是GABAB受体介导功能的强效正性增强剂，并讨论了其假定的临床应用。有人提出，这些新型调节剂可能在GABAB受体药理学中具有治疗价值，并且能够选择性地改变GABAB受体功能。变构调节剂提供了一种有吸引力的新方法来识别新的先导物，这些先导物没有与GABAB受体激动剂相关的副作用，因此可能代表了药物发现过程中的一项重大进展。
