Discovery of Histamine H3 Antagonists for the Treatment of Cognitive Disorders and Alzheimer's Disease
Discovery of Histamine H3 Antagonists for the Treatment of Cognitive Disorders and Alzheimer's Disease
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DOI：
10.1124/jpet.110.166876
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发表时间：
2011-01-01
影响因子：
3.5
通讯作者：
Cowart, Marlon D.
中科院分区：
文献类型：
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作者：
Brioni, Jorge D.;Esbenshade, Tim A.;Cowart, Marlon D.
H-3拮抗剂增加脑组胺、乙酰胆碱、去甲肾上腺素和多巴胺的释放，这些神经递质被认为可以调节认知过程。释放大脑组胺的能力支持对注意力和警觉性的影响，但组胺也调节其他认知领域，如短期和长期记忆。若干H-3拮抗剂，包括1-{3-[3-（4-氯苯基）丙氧基}哌啶盐酸盐（BF2.649）、(1R,3R)- n-乙基-3-氟-3-[3-氟-4-（吡罗烷-1-基甲基）苯基]环丁烷-1-羧酰胺（PF-03654746）、6-[（3-环丁基-2,3,4,5-四氢- 1h -3-苯甲平-7-基）氧]- n-甲基-3-吡啶甲酰胺盐酸盐（GSK189254）、MK-0249（结构尚未披露）、JNJ-17216498（结构尚未披露）和ABT-288（结构尚未披露）。已发展到临床领域，为治疗人类认知障碍提供了潜在的途径。H-3拮抗剂在人类中表现出促进觉醒的作用，在发作性睡症患者中也表现出疗效，表明了靶点参与，但其中一些拮抗剂对注意力缺陷多动障碍患者和精神分裂症患者无效。临床前研究也表明，H-3拮抗剂激活细胞内信号通路，可能改善阿尔茨海默病的认知疗效和疾病改善作用。正在进行的临床研究将能够确定H-3拮抗剂治疗人类认知障碍的效用。
H-3 antagonists increase the release of brain histamine, acetylcholine, noradrenaline, and dopamine, neurotransmitters that are known to modulate cognitive processes. The ability to release brain histamine supports the effect on attention and vigilance, but histamine also modulates other cognitive domains such as short-term and long-term memory. A number of H-3 antagonists, including 1-{3-[3-(4-chlorophenyl)propoxy]propyl} piperidine hydrochloride (BF2.649), (1R,3R)-N-ethyl-3-fluoro-3-[3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl]cyclobutane-1-carboxamide (PF-03654746), 6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridinecarboxamide hydrochloride (GSK189254), MK-0249 (structure not yet disclosed), JNJ-17216498 (structure not yet disclosed), and ABT-288 (structure not yet disclosed), have advanced to the clinical area for the potential treatment of human cognitive disorders. H-3 antagonists exhibited wake-promoting effects in humans and efficacy in narcoleptic patients, indicating target engagement, but some of them were not efficacious in patients suffering from attention-deficit hyperactivity disorder and schizophrenic patients. Preclinical studies have also shown that H-3 antagonists activate intracellular signaling pathways that may improve cognitive efficacy and disease-modifying effects in Alzheimer's disease. Ongoing clinical studies will be able to determine the utility of H-3 antagonists for the treatment of cognitive disorders in humans.