GABAA受体苯二氮卓类变构部位的部分逆激动剂β-卡波林FG-7142的药理学:神经化学、神经生理和行为效应

Andrew K. Evans, Christopher A. Lowry
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引用次数: 82

摘要

鉴于苯二氮卓类药物在治疗焦虑障碍中的作用,β-碳胺类药物在GABAA受体苯二氮卓变构部位的作用范围从完全激动剂到完全逆激动剂,可以为焦虑相关生理和行为的神经机制提供有价值的见解。FG-7142是苯二氮卓类变构部位的部分逆激动剂,对含α1亚基的GABAA受体具有最高的亲和力,尽管它没有选择性。FG-7142在含α1亚基GABAA受体介导的gaba诱导的氯通量调节中也具有最高的效果。FG-7142激活已知的焦虑相关神经网络,并与该网络中的血清素能、多巴胺能、胆碱能和去甲肾上腺素能调节系统相互作用。FG-7142在包括人类在内的许多哺乳动物和非哺乳动物物种的各种实验范式中已被证明可诱导焦虑相关的行为和生理反应。FG-7142在焦虑相关的行为范式中具有促进冲突的作用,调节注意过程,并增加心加速交感反应性和神经内分泌反应性。急性和慢性FG-7142治疗均具有惊厥前作用,上调皮质肾上腺素受体,降低GABA和β-卡伯碱激动剂的后续作用,并增加后续GABAA受体拮抗剂和β-卡伯碱逆激动剂的有效性。FG-7142作为一种部分逆激动剂,可以帮助阐明苯二氮卓类药物结合位点完全激动作用的个体成分,并可能用于识别参与特定行为和生理反应的特定GABAA受体亚型。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Pharmacology of the β-Carboline FG-7142, a Partial Inverse Agonist at the Benzodiazepine Allosteric Site of the GABAA Receptor: Neurochemical, Neurophysiological, and Behavioral Effects

Pharmacology of the β-Carboline FG-7142, a Partial Inverse Agonist at the Benzodiazepine Allosteric Site of the GABAA Receptor: Neurochemical, Neurophysiological, and Behavioral Effects

Given the well-established role of benzodiazepines in treating anxiety disorders, β-carbolines, spanning a spectrum from full agonists to full inverse agonists at the benzodiazepine allosteric site for the GABAA receptor, can provide valuable insight into the neural mechanisms underlying anxiety-related physiology and behavior. FG-7142 is a partial inverse agonist at the benzodiazepine allosteric site with its highest affinity for the α1 subunit-containing GABAA receptor, although it is not selective. FG-7142 also has its highest efficacy for modulation of GABA-induced chloride flux mediated at the α1 subunit-containing GABAA receptor. FG-7142 activates a recognized anxiety-related neural network and interacts with serotonergic, dopaminergic, cholinergic, and noradrenergic modulatory systems within that network. FG-7142 has been shown to induce anxiety-related behavioral and physiological responses in a variety of experimental paradigms across numerous mammalian and non-mammalian species, including humans. FG-7142 has proconflict actions across anxiety-related behavioral paradigms, modulates attentional processes, and increases cardioacceleratory sympathetic reactivity and neuroendocrine reactivity. Both acute and chronic FG-7142 treatment are proconvulsive, upregulate cortical adrenoreceptors, decrease subsequent actions of GABA and β-carboline agonists, and increase the effectiveness of subsequent GABAA receptor antagonists and β-carboline inverse agonists. FG-7142, as a partial inverse agonist, can help to elucidate individual components of full agonism of benzodiazepine binding sites and may serve to identify the specific GABAA receptor subtypes involved in specific behavioral and physiological responses.

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