Dual-Acting Drugs: an in vitro Study of Nonimidazole Histamine H3 Receptor Antagonists Combining Anticholinesterase Activity
Dual-Acting Drugs: an in vitro Study of Nonimidazole Histamine H3 Receptor Antagonists Combining Anticholinesterase Activity
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DOI：
10.1002/cmdc.201000008
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发表时间：
2010-07-10
期刊：
影响因子：
3.4
通讯作者：
Bertoni, Simona
中科院分区：
文献类型：
--
作者：
Incerti, Matteo;Flammini, Lisa;Bertoni, Simona
结合H-3拮抗剂和抗胆碱酯酶特性的双作用化合物目前正在成为治疗以胆碱能缺陷为主要特征的多因素疾病（如阿尔茨海默病）的一种新颖而有前景的治疗方法。一系列新的非咪唑H-3配体是通过对H-3八甲基、壬基和十亚甲基双哌替啶-H-3拮抗剂的化学处理而开发出来的，这些药物已成为先前研究的主题。对这些化合物进行了体外结合亲和力、拮抗效力、对啮齿动物和人组胺H-3受体的选择性、对大鼠脑胆碱酯酶的抑制活性、体内中枢神经系统通路和胆碱模拟作用的评估。在目前的系列中，四氢氨基吖啶杂合物18是最具吸引力的分子之一，它协同结合了纳米摩尔和选择性H-3拮抗剂，具有显著的抗胆碱酯酶活性。从这个最初的起点出发，希望未来的研究将导致双作用化合物，可以选择性地增强中枢胆碱能神经传递，从而促进认知障碍的治疗。
Dual acting compounds that combine H-3 antagonism with anticholinesterase properties are currently emerging as a novel and promising therapeutic approach in the treatment of multifactorial disorders primarily characterized by cholinergic deficits such as Alzheimer's disease A series of novel nonimidazole H-3 ligands was developed from the chemical manipulation of H-3 octa, nona, and decamethylene bis piperidines-H-3 antagonists that had been the subject of previous invesstigations. These compounds were evaluated for in vitro binding affinity, antagonistic potency, and selectivity at rodent and human histamine H-3 receptors, inhibitory activity at rat brain cholinesterase, and in vivo CNS access and cholinomimetic effects. Within the present series, the tetrahydroaminoacridine hybride 18 stands out as one of the most attractive moleculesynergistically combining nanomolar and selective H-3 antagonism with remarkable anticholinesterase activity. From this original starting point, it is hoped that future investigations will lead to dual-acting compounds that can selectively enhance central cholinergic neurotransmission and thus facilitate the treatment of cognitive disorders.