Design and in vitro pharmacology of a selective gamma-aminobutyric acidC receptor antagonist.
Design and in vitro pharmacology of a selective gamma-aminobutyric acidC receptor antagonist.
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发表时间：
1996-10
影响因子：
3.6
通讯作者：
D. Ragozzino;Richard M. Woodward;Y. Murata;F. Eusebi;Larry E. Overman;Ricardo Miledi
中科院分区：
文献类型：
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作者：
D. Ragozzino;Richard M. Woodward;Y. Murata;F. Eusebi;Larry E. Overman;Ricardo Miledi
在哺乳动物中，抑制性神经递质γ-氨基丁酸（GABA）的受体分为三个药理学类别，分别表示为GABAA、GABAB和GABAC。GABAC受体通过其对GABAA受体拮抗剂荷包牡丹碱和GABAB受体激动剂（-）-巴氯芬的不敏感性来定义。GABAC受体可能是一组异质性蛋白质。最广泛研究的哺乳动物GABAC受体是在外视网膜的神经元中发现的那些。这些受体是由p亚基组成的GABA门控Cl-通道，其中有两种亚型。GABAC受体的生理功能在很大程度上是未知的;为了确定功能，具有GABAC选择性配体将是有用的。在以前的研究中，我们发现异谷瓦辛，GABAA选择性激动剂，3-氨丙基-（甲基）膦酸（3-APMPA），GABAB选择性激动剂，显示出对视网膜GABAC受体的亲和力。特别是，3-APMPA是一种具有低微摩尔效力的拮抗剂（Kb约为1 μ M）。在这里，我们报告的合成和药理学特性的（1，2，5，6-四氢吡啶-4-基）甲基次膦酸（TPMPA），异guguvacine和3-APMPA的混合物，旨在保留GABAC受体的亲和力，但不与GABAA或GABAB受体相互作用。电分析表明TPMPA是非洲爪蟾卵母细胞中表达的克隆人mu 1 GABAC受体的竞争性拮抗剂（Kb约为2 μ M）。TPMPA作为在卵母细胞中表达的大鼠脑GABAA受体的抑制剂弱> 100倍（Kb约320 μ M），并且对在大鼠海马切片中测定的GABAB受体仅具有弱激动剂活性（EC 50约500 μ M）。TPMPA应该是一个有用的药理学探针，调查GABAC受体的功能，在视网膜外层和任何其他地区的神经系统中，这些类型的受体存在。
In mammals, receptors for the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) are divided into three pharmacological classes, which are denoted GABAA, GABAB, and GABAC. GABAC receptors are defined by their insensitivity to the GABAA receptor antagonist bicuculline and the GABAB receptor agonist (-)-baclofen. GABAC receptors probably are a heterogeneous group of proteins. The most extensively studied mammalian GABAC receptors are those found in neurons of the outer retina. These receptors are GABA-gated Cl- channels comprised of p subunits, of which there are two subtypes. The physiological functions served by GABAC receptors are largely unknown; to determine the functions, it would be useful to have GABAC-selective ligands. In a previous study, we found that isoguvacine, a GABAA-selective agonist, and 3-aminopropyl-(methyl)phosphinic acid (3-APMPA), a GABAB-selective agonist, show affinity for retinal GABAC receptors. In particular, 3-APMPA is an antagonist with low micromolar potency (Kb approximately 1 microM). Here, we report the synthesis and pharmacological characterization of (1,2,5,6-tetrahydropyridine-4-yl)methylphosphinic acid (TPMPA), a hybrid of isoguvacine and 3-APMPA designed to retain affinity for GABAC receptors but not to interact with GABAA or GABAB receptors. Electrical assays show that TPMPA is a competitive antagonist of cloned human mu 1 GABAC receptors expressed in Xenopus laevis oocytes (Kb approximately 2 microM). TPMPA is > 100-fold weaker as an inhibitor of rat brain GABAA receptors expressed in oocytes (Kb approximately 320 microM) and has only weak agonist activity on GABAB receptors assayed in rat hippocampal slices (EC50 approximately 500 microM). TPMPA should be a useful pharmacological probe with which to investigate GABAC receptor function in the outer retina and in any other areas of the nervous system in which these types of receptor are present.