摘要
背景:近几年来,5-羟色胺6受体(5-HT6受体,5-HT6R)已成为治疗神经性疾病(包括阿尔茨海默症(AD)和精神分裂症)的有望治疗靶点。5-HT6受体被猜想参与学习,记忆,认知过程,使用5-HT6R拮抗剂能有效修复动物模型的认知和记忆。许多选择性5-HT6R配体如今正在进行AD治疗的临床试验。 方法:我们描述了新型高选择性强效5-HT6R拮抗剂:AVN-322作为治疗AD患者记忆和认知并发虚弱和精神分裂症的抗精神病物质的候选药物的预临床发展。在手稿中,我们描述了它的体内和体外效果,(药物的)吸收、分布、代谢与排泄,动物和人体药物代谢动力学以及毒性。 结果:在中度皮尔摩范围时表现出高亲和力,先导化合物比现在正在临床实验的参考药物表现出更好的选择性指数。AVN-322表现出高口服生物利用度和很好的血脑屏障(BBB)穿透力。体内试验揭示了它的良好增强认知的效用。AVN-322显著修复由东莨菪碱和MK-801诱发的认知功能失调并有抗精神病的可能。 结论:考虑到其良好的安全性和药物代谢动力学,AVN-322可以合理的被认为是治疗神经系统疾病(如AD和/或精神分裂症 )的新型候选药物。
关键词: 阿尔茨海默症,认知,中枢神经系统疾病,5-羟色胺6受体拮抗剂,记忆
Current Alzheimer Research
Title:AVN-322 is a Safe Orally Bio-Available Potent and Highly Selective Antagonist of 5-HT6R with Demonstrated Ability to Improve Impaired Memory in Animal Models
Volume: 14 Issue: 3
Author(s): Alexandre V. Ivachtchenko, Yan A. Ivanenkov, Mark S. Veselov, I. M. Okun.
Affiliation:
关键词: 阿尔茨海默症,认知,中枢神经系统疾病,5-羟色胺6受体拮抗剂,记忆
摘要: Background: In recent years, 5-hydroxytryptamine subtype 6 receptor (5-HT6 receptor, 5- HT6R) has emerged as a promising therapeutic target for the treatment of neuropathological disorders, including Alzheimer’s disease (AD) and schizophrenia. 5-HT6 receptors were hypothesized to be implicated in the processes of learning, memory, and cognition with 5-HT6R antagonists being effective in animal models of cognition and memory impairment. Several selective 5-HT6R ligands are currently undergoing clinical trials for treatment of AD.
Methods: We describe results of preclinical development of a novel and highly selective and potent 5- HT6R antagonist, AVN-322, as a clinical candidate for the treatment of AD to improve concurrent debilitation of memory and cognition in the AD patients, and schizophrenia as a substance with antipsychotic effect. In the manuscript, we present its in vitro and vivo efficacy, ADME, pharmacokinetics in animals and in humans, and toxicity. Results: While having high binding affinity in medium picomolar range, the lead compound demonstrates substantially better selectivity index then the reference drug candidates currently being tested in clinical studies. AVN-322 showed high oral bioavailability and favorable blood-brain barrier (BBB) penetration. In vivo testing revealed its clear cognition enhancing effect. AVN-322 significantly restored both scopolamine- and MK-801-induced cognitive dysfunction and demonstrated antipsychotic potential. Conclusion: Taking into account its good safety profile and favorable pharmacokinetics, AVN-322 can be reasonably considered as a novel drug candidate for the treatment of neurological disorders such as AD and/or schizophrenia.Export Options
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Cite this article as:
Alexandre V. Ivachtchenko, Yan A. Ivanenkov, Mark S. Veselov, I. M. Okun. , AVN-322 is a Safe Orally Bio-Available Potent and Highly Selective Antagonist of 5-HT6R with Demonstrated Ability to Improve Impaired Memory in Animal Models, Current Alzheimer Research 2017; 14 (3) . https://dx.doi.org/10.2174/1567205013666161108105005
DOI https://dx.doi.org/10.2174/1567205013666161108105005 |
Print ISSN 1567-2050 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5828 |
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