药效基因/ GABA (A)受体模型/ BzR亚型(alpha1beta3gamma2、alpha5beta3gamma2 alpha6beta3gamma2)通过全面ligand-mapping方法。

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他X,黄问马C,刘R, S,天,温格GR,麦凯南R,库克JM

药效基因/ GABA (A)受体模型/ BzR亚型(alpha1beta3gamma2、alpha5beta3gamma2 alpha6beta3gamma2)通过全面ligand-mapping方法。

J地中海化学。2000年1月13日,43 (1):71 - 95。

PubMed ID

10633039 (在PubMed

]

文摘

药效团/受体模型三重组GABA (A) / BzR亚型(alpha1beta3gamma2、alpha5beta3gamma2 alpha6beta3gamma2)已经建立了通过一个特区ligand-mapping方法。这项研究是基于151年的亲和力BzR在五个不同的配体(alpha1-3 5 6 beta3gamma2)重组GABA (A) / BzR受体亚型至少九个不同结构的家庭。考试包括卷的α- alpha5和alpha6-containing亚型表明地区L (2) alpha5-containing亚型出现更大的规模比其他类似地区的受体亚型。地区L (Di),相比之下,似乎是更大的比其他两个亚型α1亚型。此外,地区L (3) alpha6亚型很小或不存在在这个diazepam-insensitive亚型(见图16)比其他亚型。使用这些亚型的药效团/受体模型导致了小说BzR配体的设计(见27)alpha5beta3gamma2受体亚型选择性。alpha5-Selective配体27当直接注入海马体增强记忆在一个范式(贝利et al .,未发表的观察);然而,系统性管理9或27到动物并没有提供一个可观测的增强。这个结果与观察完全同意刘(1996)。它已被证明(刘,1996; Wisden et al., 1992) that in the central nervous system of the rat (as well as monkeys and pigeons) there are several native subtypes of the GABA(A) receptor which exhibit different functions, regional distributions, and neuronal locations. Although 27 binds more potently at alpha5beta3gamma2 receptor subtypes and is clearly an inverse agonist (Liu et al., 1996; Liu, 1996), it is possible that this ligand acts as an agonist at one or more subtypes. Liu (1996) clearly showed that a number of imidazobenzodiazepines were negative modulators at one subtype and agonists at another. Therefore, selectivity for a particular subtype at this point is not sufficient to rule out some physiological effect at other GABA(A)/BzR subtypes. The inability of 27 to potentiate memory when given systemically is again in support of this hypothesis, especially since alpha1beta2gamma2 subtypes are distributed throughout the brain (Wisden et al., 1992). A drug delivered systemically is far more likely to interact with all subtypes than one delivered to a specific brain region. This observation (systemic vs intrahippocampal) provides further support for the design of more subtype-specific ligands at the BzR to accurately define their pharmacology, one key to the design of new drugs with fewer side effects.

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绑定属性

药物	目标	财产	测量	pH值	温度(°C)
Flumazenil	γ-氨基丁酸受体亚基gamma-2	Ki (nM)	0.9	N /一个	N /一个	细节
唑吡坦	γ-氨基丁酸受体亚基alpha 3	Ki (nM)	383年	N /一个	N /一个	细节
唑吡坦	γ-氨基丁酸受体亚基gamma-2	Ki (nM)	156年	N /一个	N /一个	细节