A synthetic agonist at the orphanin FQ/nociceptin receptor ORL1: Anxiolytic profile in the rat
A synthetic agonist at the orphanin FQ/nociceptin receptor ORL1: Anxiolytic profile in the rat
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DOI：
10.1073/pnas.090514397
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发表时间：
2000-04-25
影响因子：
11.1
通讯作者：
Kilpatrick, G
中科院分区：
文献类型：
--
作者：
Jenck, F;Wichmann, J;Kilpatrick, G
本文报道了一种非肽类、选择性和脑渗透性激动剂对ORL 1受体的生物化学和行为学影响。该低分子量化合物[（1 S，3aS）-8-（2，3，3a，4.5.6-六氢-1H-非那烯-1-基）-1 -苯基-1，3，8-三氮杂螺[4.5]癸烷-4-酮]对重组人ORL 1受体具有高亲和力，对ORL 1的选择性是阿片受体家族其他成员的100倍。它是这些受体的完全激动剂，并且在大鼠中不同类型焦虑状态的一组验证模型中具有剂量依赖性抗焦虑样作用（即，升高的十字迷宫、恐惧增强的惊吓和操作性冲突）。当全身给药时，该化合物具有与苯并二氮卓类抗焦虑药如阿普唑仑或地西泮相当的功效和效力。然而，该化合物与经典的苯二氮卓类抗焦虑药的区别在于，在抗焦虑剂量（0.3 - 3 mg/kg i.p）下，缺乏有效的抗恐慌样活性，缺乏抗惊厥特性，以及对运动表现和认知功能缺乏影响。在该剂量范围内未观察到颅内自刺激性能和疼痛反应性的显著变化。较高剂量的该化合物（大于或等于10 mg/kg）诱导大鼠行为中断。这些数据证实了在低剂量下观察到的显著的抗焦虑样作用，其中局部给予脑中的FQ/痛敏肽神经肽，并支持FQ/痛敏肽在对压力的适应性行为恐惧反应中的作用。
The biochemical and behavioral effects of a nonpeptidic, selective, and brain-penetrant agonist at the ORL1 receptor are reported herein. This low molecular weight compound [(1S,3aS)-8-(2,3,3a,4.5.6-hexahydro-1H-phenalen-1-yl)-1 -phenyl-1,3,8-triazaspiro[4.5]decan-4-one) has high affinity for recombinant human ORL1 receptors and has 100-fold selectivity for ORL1 over other members of the opioid receptor family. It is a full agonist at these receptors and elicits dose-dependent anxiolytic-like effects in a set of validated models of distinct types of anxiety states in the rat (i.e., elevated plus-maze, fear-potentiated startle, and operant conflict). When given systemically, the compound has an efficacy and potency comparable to those of a benzodiazepine anxiolytic such as alprazolam or diazepam. However, this compound is differentiated from a classical benzodiazepine anxiolytic by a lack of efficient anti-panic-like activity, absence of anticonvulsant properties, and lack of effects on motor performance and cognitive function at anxiolytic doses (0.3 to 3 mg/kg i.p,). No significant change in intracranial self-stimulation performance and pain reactivity was observed in this dose range. Higher doses of this compound (greater than or equal to 10 mg/kg) induced disruption in rat behavior. These data confirm the notable anxiolytic-like effects observed at low doses with the orphanin FQ/nociceptin neuropeptide given locally into the brain and support a role for orphanin FQ/nociceptin in adaptive behavioral fear responses to stress.