Alt Andrew, Weiss Brianne, Ornstein Paul L, Gleason Scott D, Bleakman David, Stratford Robert E, Witkin Jeffrey M
Neuroscience Discovery Research and Discovery Chemistry, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285-0510, USA.
Neuropharmacology. 2007 Jun;52(7):1482-7. doi: 10.1016/j.neuropharm.2007.02.005. Epub 2007 Mar 2.
The hypothesis that kainate receptor blockade would be associated with anxiolytic-like effects was tested with a selective ligand, 3S,4aR,6S,8aR-6-((4-carboxyphenyl)methyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid (LY382884). LY382884 selectively binds the GLU(K5) kainate receptor subunit (K(b)=0.6 microM) and has 30 microM or greater affinity for cloned human AMPA receptor subtypes. The anxiolytic potential of LY382884 was tested in rats responding under a Vogel conflict procedure, a pharmacologically validated model for the prediction of antianxiety efficacy in humans. Both the benzodiazepine anxiolytic chlordiazepoxide and LY382884 increased suppressed licking without affecting rates of non-suppressed licking. In contrast, an AMPA receptor selective antagonist, 7H-1,3-dioxolo[4,5-h][2,3]benzodiazepine-7-carboxamide, 5-(4-aminophenyl)-8,9-dihydro-N,8-dimethyl-, monohydrochloride (9CI) (GYKI53655), did not increase suppressed responding. The finding that a selective GLU(K5) receptor antagonist produced anxiolytic-like effects in an animal model predictive of efficacy in humans combined with data in the literature on glutamatergic modulation of anxiety suggests that kainate receptor sensitivity to glutamate might be an important mediating event in the pathophysiological expression of anxiety states. The selective targeting of kainate receptors with an antagonist could therefore be a novel pharmacological mechanism to treat anxiety disorders.
使用选择性配体3S,4aR,6S,8aR-6-((4-羧基苯基)甲基)-1,2,3,4,4a,5,6,7,8,8a-十氢异喹啉-3-羧酸（LY382884），对红藻氨酸受体阻断与抗焦虑样效应相关的假说进行了测试。LY382884选择性结合GLU(K5)红藻氨酸受体亚基（K(b)=0.6微摩尔），对克隆的人AMPA受体亚型具有30微摩尔或更高的亲和力。在大鼠的Vogel冲突程序下对LY382884的抗焦虑潜力进行了测试，这是一种经药理学验证的预测人类抗焦虑疗效的模型。苯二氮䓬类抗焦虑药氯氮卓和LY382884均增加了被抑制的舔舐行为，而不影响未被抑制的舔舐频率。相比之下，AMPA受体选择性拮抗剂7H-1,3-二氧杂环戊烯并[4,5-h][2,3]苯并二氮杂䓬-7-甲酰胺，5-(4-氨基苯基)-8,9-二氢-N,8-二甲基-，一盐酸盐（9CI）（GYKI53655）并未增加被抑制的反应。在预测对人类疗效的动物模型中，选择性GLU(K5)受体拮抗剂产生抗焦虑样效应这一发现，结合文献中关于焦虑的谷氨酸能调节的数据，表明红藻氨酸受体对谷氨酸的敏感性可能是焦虑状态病理生理表达中的一个重要介导事件。因此，用拮抗剂选择性靶向红藻氨酸受体可能是治疗焦虑症的一种新的药理学机制。
