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首页> 外文期刊>CNS drug reviews >Clinical potential of GABAB receptor modulators.
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Clinical potential of GABAB receptor modulators.

机译：GABAB受体调节剂的临床潜力。

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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 withinits 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.
机译：主要抑制递质GABA的代谢型γ-氨基丁酸（B）（GABAB）受体与代谢型谷氨酸（mGLuRs）受体，细胞外钙敏感受体（CaSR），一些V2R信息素受体和T1R味觉受体一起属于3 G蛋白偶联受体（GPCR）家族。已知GABA B受体控制神经元兴奋性并调节突触神经传递，在许多生理活动中起着非常重要的作用。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，精神分裂症和药物成瘾。为了形成功能性受体实体，GABAB受体必须以由两个具有7个跨膜蛋白的GABAB1和GABAB2受体亚型组成的异二聚体形式存在，并且这些亚基来自不同的基因。 GABAB1亚基在其细胞外N端结合内源性配体，而GABAB2亚基不仅是GABAB1亚基正确转运至细胞表面所必需的，而且还负责受体与其同源G蛋白的相互作用。近来，变构调节被认为是获得药物作用选择性的另一种药理方法。现在已经普遍接受的是，作用于变构位点的调节剂为作用于GPCR的亚型选择剂的开发提供了新的视角。这些试剂与与高度保守的激动剂结合区完全分开的变构结合位点相互作用。在这篇综述中，我们介绍了基于铅化合物芬迪林的一类新的苯基烷基胺，它们是GABA B受体介导的功能的有效正增效剂，并讨论了其假定的临床应用。提出这些新的调节剂在GABA B受体药理学中可能具有治疗价值，并且能够选择性地修饰GABA B受体功能。变构调节剂正在提供一种吸引人的新颖方法来鉴定新的先导，这些新的先导没有与GABAB受体激动剂相关的副作用，因此可能代表着药物开发过程的重大进展。

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