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受体，调控hitamine的合成和释放。近年来，H3受体被发现存在于外周和其他神经元系统中。在本研究中，我们检测了组胺H3配体对哮喘和痴呆模型动物的影响。以衰老加速小鼠为研究对象，采用穿梭箱法评估其学习记忆能力。异常老龄小鼠（P/8）习得学习任务较慢，但给予H3拮抗剂硫哌丁胺后，习得速度降至正常老龄小鼠水平（R/1）。一个胆碱能系统被阿波拉胺破坏的痴呆模式小鼠，通过硫哌丁胺的管理，在一个升高的正迷宫测试中表现出改善。在各种哮喘模型中，(R)- α -甲基组胺和亚米特等H3激动剂均不能获得明确的结果。可能需要一种更合适的分析模型来评价H3激动剂。评价了绿十字公司开发的一系列新型H3拮抗剂对小鼠电惊厥的抑制作用，其中AQ-145的抑制作用最强。在大鼠体内测量了硫哌丁胺和(R)- α -甲基组胺的药效学参数，表明这些化合物对大脑的渗透不是很好。在这些研究过程中，发现H3拮抗剂在小鼠最大电休克模型中具有抗惊厥作用。总之，H3拮抗剂可能是未来开发抗癫痫和抗痴呆药物的靶点。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.