Histamine H3R Antagonists: From Scaffold Hopping to Clinical Candidates
Histamine H3R Antagonists: From Scaffold Hopping to Clinical Candidates
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DOI：
10.1007/978-3-319-40308-3_5
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发表时间：
2016-01-01
期刊：
影响因子：
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通讯作者：
Stark, H.
中科院分区：
文献类型：
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作者：
Sadek, B.;Lazewska, D.;Stark, H.
组胺H-3受体（H3 R）属于G蛋白偶联受体家族，主要表达于中枢神经系统（CNS）。自从Arrang等人发现它以来，它通过作为神经递质释放的致动器发挥关键作用而与几种中枢神经系统疾病相关，例如，多巴胺乙酰胆碱去甲肾上腺素或血清素因此，大量的H3 R拮抗剂已被研究其在肥胖症、抑郁症、情绪障碍、神经性疼痛和睡眠-觉醒障碍中的潜在治疗适用性（包括发作性睡病）以及认知和CNS相关的感觉运动缺陷障碍，如帕金森病、注意力缺陷多动障碍、阿尔茨海默病、精神分裂症、酒精成瘾、能量稳态、癫痫、阻塞性睡眠呼吸暂停、糖尿病性神经性疼痛、图雷特综合征和僵住症。到目前为止，已经合成了许多结构不同的H3 R拮抗剂并对其进行了初步评价。尽管化合物的多样性很高，但这些结构具有相似的结构模式。药效团含有叔碱性胺（假定与螺旋3中的保守天冬氨酸114相互作用）、接头（通常为线性丙氧基链或结构受限的）、中心核心和“东部”任意区域（具有高度多样性，例如不同大小的第二碱性、酸性、亲脂性或极性部分）。
The histamine H-3 receptor (H3R), belonging to the family of G-proteincoupled receptors, is predominantly expressed in the central nervous system (CNS). Since its discovery by Arrang et al., it was related to several central nervous system diseases by playing a key role as actuator of neurotransmitter release for, e.g., dopamine, acetylcholine, noradrenaline, or serotonin. Therefore, a huge number of H3R antagonists have been investigated on their potential therapeutic applicability in obesity, depression, mood disorders, neuropathic pain, and sleep-wake disorders (including narcolepsy) as well as cognitive and CNS-linked sensorimotor deficit disorders such as Parkinson's disease, attention deficit hyperactivity disorder, Alzheimer's disease, schizophrenia, alcohol addiction, energy homeostasis, epilepsy, obstructive sleep apnea, diabetic neuropathic pain, Tourette's syndrome, and catalepsy. So far, many structurally diverse H3R antagonists have been synthesized and pharmacologically evaluated. Despite a high diversity of compounds, these structures share a similar construction pattern. The pharmacophore contains a tertiary basic amine (postulated to interact with the conserved aspartate 114 in helix 3), a linker (commonly a linear propyloxy chain or structurally constrained), a central core, and "the eastern" arbitrary region (with high diversity such as second basic, acidic, lipophilic, or polar moieties of different sizes).