Drug development with histamine H3 receptor as a target

组胺H3受体是中枢组胺神经元系统的突触前自身受体，调节组胺的合成和释放。近年来，H3受体被发现定位于外周和其他神经系统。在这项研究中，我们研究了组胺H3配体对哮喘和痴呆模型动物的影响。采用快速老化小鼠，采用穿梭箱对其学习记忆能力进行评价。异常衰老品系(P/8)小鼠学习任务的完成较慢，但给予H3拮抗剂硫代巴比妥钠可使其恢复到正常衰老小鼠(R/1)的水平。一种痴呆模型小鼠，其胆碱能系统被阿波拉明破坏，在高架+迷宫测试中，给予硫代巴比妥钠后表现出改善。在不同的哮喘模型中，H3激动剂如(R)-α-甲基组胺和亚胺都不能取得明显的效果。对于H3激动剂的评价，可能需要一个更合适的分析模型。评价了绿十字公司开发的一系列新的H3拮抗剂对小鼠电惊厥的抑制作用，其中以AQ-145效果最好。对硫代巴比妥钠和(R)-α-甲基组胺在大鼠体内的药效学参数进行了测定，结果表明这些化合物对脑的渗透性不好。在研究过程中，发现H3拮抗剂在小鼠极大电休克模型上具有抗惊厥作用。综上所述，H3拮抗剂可能是未来抗癫痫和抗痴呆药物开发的靶点。然而，为此，有必要进行更多的基础研究。

Histamine H3 receptor is a presynaptic autoreceptor of the central histaminegic neuron system and regulates the synthesis and release of hitamine. Recently, H3 receptor was found to locate in the periphery and other neuron systems. In this recearch, we examined the effects of histamine H3 ligands on model animals of asthma and dementia. Using senescence accelerated mice, we evaluated their learning and memory ability by a shuttle box. Abnormally aged strain (P/8) mice were slow in acqusition of learning task, but the administration of H3 antagonist, thioperamide, facilitated the rate to the level of normal aged mice (R/1). A dementia mode mouse whose cholinergic system was destroyed by acopolamine showed an improvement in an elevated plus maze test by the administration of thioperamide. In various models of asthma, wa could not obtain clear results by H3 agonists such as (R)-alpha-methylhistamine and imitet. Probably a more suitable model of analysis is reguired for the evaluation of H3 agonists. A series of new H3 antagonists developed by Green Cross Co. were eraluated for their potency of inhibition of electric convulsion of mice : Among them AQ-145 was the most potent. Pharmacodynamic parameters of thioperamide and (R)-alpha-methylhistamine were measured in rats, showing that the penetration of these compounds into the brain is not good. During the course of these studies, it was found that H3 antagonists had anticonvulsive action in maximal electroshock model of mice. In summary, H3 antagonists may be a target for future development of antiepileptic and anti-dementia agents. However, to this purpose, it is necessary to carry out more basic studies.