Laboratoire de Neurobiologie, Université d'Orléans, BP 6759, F-45067 Orléans Cedex 2, France.
Neuroscience. 2010 Sep 1;169(3):1337-46. doi: 10.1016/j.neuroscience.2010.05.040. Epub 2010 May 24.
A novel pyridine derivative, 8-{4-[(6-methoxy-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-3-ylmethyl)-amino]-butyl}-8-aza-spiro[4.5]decane-7,9-dione hydrochloride, termed JB-788, was designed to selectively target 5-HT(1A) receptors. In the present study, the pharmacological profile of JB-788 was characterized in vitro using radioligands binding tests and in vivo using neurochemical and behavioural experiments. JB-788 bound tightly to human 5-HT(1A) receptor expressed in human embryonic kidney 293 (HEK-293) cells with a K(i) value of 0.8 nM. Its binding affinity is in the same range as that observed for the (+/-)8-OH-DPAT, a reference 5HT(1A) agonist compound. Notably, JB-788 only bound weakly to 5-HT(1B) or 5-HT(2A) receptors and moreover the drug displayed only weak or indetectable binding to muscarinic, alpha(2), beta(1) and beta(2) adrenergic receptors, or dopaminergic D(1) receptors. JB-788 was found to display substantial binding affinity for dopaminergic D(2) receptors and, to a lesser extend to alpha(1) adrenoreceptors. JB-788 dose-dependently decreased forskolin-induced cAMP accumulation in HEK cells expressing human 5-HT(1A), thus acting as a potent 5-HT(1A) receptor agonist (E(max.) 75%, EC(50) 3.5 nM). JB-788 did not exhibit any D(2) receptor agonism but progressively inhibited the effects of quinpirole, a D(2) receptor agonist, in the cAMP accumulation test with a K(i) value of 250 nM. JB-788 induced a weak change in cAMP levels in mouse brain but, like some antipsychotics, transiently increased glycogen contents in various brain regions. Behavioral effects were investigated in mice using the elevated plus-maze. JB-788 was found to increase the time duration spent by animals in anxiogenic situations. Locomotor hyperactivity induced by methamphetamine in mouse, a model of antipsychotic activity, was dose-dependently inhibited by JB-788. Altogether, these results suggest that JB-788 displays pharmacological properties, which could be of interest in the area of anxiolytic and antipsychotic drugs.
一种新型吡啶衍生物，8-{-4-[(6-甲氧基-2,3-二氢-[1,4]二氧杂[2,3-b]吡啶-3-基甲基)-氨基]-丁基}-8-氮杂螺[4.5]癸烷-7,9-二酮盐酸盐，称为 JB-788，被设计为选择性靶向 5-HT(1A)受体。在本研究中，使用放射性配体结合试验和神经化学和行为实验在体外研究了 JB-788 的药理学特征。JB-788 与在人胚肾 293（HEK-293）细胞中表达的人 5-HT(1A)受体紧密结合，K(i)值为 0.8 nM。其结合亲和力与（+/-）8-OH-DPAT 相当，（+/-）8-OH-DPAT 是一种参考 5-HT(1A)激动剂化合物。值得注意的是，JB-788 仅弱结合 5-HT(1B)或 5-HT(2A)受体，并且药物对毒蕈碱、α(2)、β(1)和β(2)肾上腺素能受体或多巴胺 D(1)受体的结合仅弱或不可检测。JB-788 被发现对多巴胺 D(2)受体具有显著的结合亲和力，并且对α(1)肾上腺素能受体的亲和力较低。JB-788 剂量依赖性地降低表达人 5-HT(1A)的 HEK 细胞中福司可林诱导的 cAMP 积累，因此作为一种有效的 5-HT(1A)受体激动剂（E(max.)75%，EC(50)3.5 nM）。JB-788 没有表现出任何 D(2)受体激动作用，但在 cAMP 积累试验中逐渐抑制了喹吡罗（D(2)受体激动剂）的作用，K(i)值为 250 nM。JB-788 可在小鼠脑中引起 cAMP 水平的微弱变化，但与一些抗精神病药一样，可短暂增加各种脑区的糖原含量。使用高架十字迷宫在小鼠中研究了行为效应。发现 JB-788 可增加动物在焦虑状态下的持续时间。在小鼠中，通过苯丙胺诱导的运动过度，一种抗精神病活性模型，被 JB-788 剂量依赖性抑制。总的来说，这些结果表明 JB-788 具有药理学特性，这可能对抗焦虑和抗精神病药物领域有兴趣。
