Antianxiety and antidepressant-like effects of AC-5216, a novel mitochondrial benzodiazepine receptor ligand
Antianxiety and antidepressant-like effects of AC-5216, a novel mitochondrial benzodiazepine receptor ligand
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DOI：
10.1038/sj.bjp.0705681
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发表时间：
2004-08-01
影响因子：
7.3
通讯作者：
Oka, M
中科院分区：
文献类型：
--
作者：
Kita, A;Kohayakawa, H;Oka, M
我们研究了一种新型线粒体苯二氮卓受体（MBR）配体n-苄基- n-乙基-2-（7,8-二氢-7-甲基-8-氧-2-苯基- 9h -嘌呤-9-基）乙酰胺（AC-5216）在多种动物模型中产生抗焦虑和抗抑郁作用的能力AC-5216对大鼠全脑mbr （K-i为0.297 nM）、大鼠胶质瘤细胞（IC50为3.04 nM）和人胶质瘤细胞（IC50为2.73 nM）具有较高的亲和力，但对中枢苯二氮卓类受体等其他主要受体的亲和力可忽略AC-5216分别以0.1-3、0.003-0.01和0.01-0.3 mg kg（-1）的剂量在大鼠vogel型冲突试验、小鼠明暗箱和社会互动试验中产生抗焦虑作用。MBR拮抗剂PK11195可拮抗AC-5216的这些作用。小鼠强迫游泳测试,ac - 5216(3-30毫克公斤(1)、订单)减少了固定时间,和这种效应被PK11195.4 ac - 5216没有myorelaxant效果,不影响内存或延长hexobarbitone-induced睡在老鼠,即使在剂量高达1000毫克公斤(1),订单。尽管它稍微延长ethanol-induced睡眠时间在1000毫克公斤(1),ac - 5216(1 - 100毫克公斤(1),订单)。河鼠electroencephalogram.5没有产生明显的变化这些结果表明，AC-5216产生抗焦虑和抗抑郁样作用，这是由MBR介导的，但不会引起通常与传统苯二氮卓类药物相关的副作用。因此，AC-5216显示出治疗焦虑和抑郁等压力相关疾病的潜力。
1 We investigated the ability of N-benzyl-N-ethyl-2-(7,8-dihydro-7-methyl-8-oxo-2-phenyl-9H-purin-9-yl) acetamide (AC-5216), a novel mitochondrial benzodiazepine receptor (MBR) ligand, to produce anti-anxiety and antidepressant-like effects in various animal models.2 AC-5216 showed high affinity for MBRs prepared from rat whole brain (K-i 0.297 nM), rat glioma cells (IC50 3.04 nM) and human glioma cells (IC50 2.73 nM), but only negligible affinity for the other main receptors including central benzodiazepine receptors.3 AC-5216 produced anti-anxiety effects in the Vogel-type conflict test in rats, and in the light/dark box and social interaction tests in mice at 0.1-3, 0.003-0.01 and 0.01-0.3 mg kg(-1), p.o., respectively. These effects of AC-5216 were antagonized by PK11195, an MBR antagonist. In the forced swimming test in rats, AC-5216 (3-30 mg kg(-1), p.o.) reduced the immobility time, and this effect was blocked by PK11195.4 AC-5216 had no myorelaxant effects, did not affect the memory or prolong hexobarbitone-induced sleep in mice, even at doses as high as 1000 mg kg(-1), p.o. Although it did slightly prolong the ethanol-induced sleep time at 1000 mg kg(-1), AC-5216 (1-100 mg kg(-1), p.o.) produced no distinct change in the rat electroencephalogram.5 These results indicate that AC-5216 produces anti-anxiety and antidepressant-like effects that are mediated by MBR, but does not cause the side effects normally associated with conventional benzodiazepines. Hence, AC-5216 shows potential for the treatment of stress-related disorders including anxiety and depression.