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一种具有认知增强活性的新型血清素 5-HT 受体拮抗剂——卤键相互作用对稳定结合的重要性。

A new serotonin 5-HT receptor antagonist with procognitive activity - Importance of a halogen bond interaction to stabilize the binding.

机构信息

Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, E-28040 Madrid, Spain.

Laboratori de Medicina Computacional, Unitat de Bioestadística, Facultat de Medicina, Universitat Autònoma de Barcelona, E-08193 Bellaterra, Spain.

出版信息

Sci Rep. 2017 Jan 24;7:41293. doi: 10.1038/srep41293.

DOI:10.1038/srep41293
PMID:28117458
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5259792/
Abstract

Serotonin 5-HT receptor has been proposed as a promising therapeutic target for cognition enhancement though the development of new antagonists is still needed to validate these molecules as a drug class for the treatment of Alzheimer's disease and other pathologies associated with memory deficiency. As part of our efforts to target the 5-HT receptor, new benzimidazole-based compounds have been designed and synthesized. Site-directed mutagenesis and homology models show the importance of a halogen bond interaction between a chlorine atom of the new class of 5-HT receptor antagonists identified herein and a backbone carbonyl group in transmembrane domain 4. In vitro pharmacological characterization of 5-HT receptor antagonist 7 indicates high affinity and selectivity over a panel of receptors including 5-HT subtype and hERG channel, which suggests no major cardiac issues. Compound 7 exhibited in vivo procognitive activity (1 mg/kg, ip) in the novel object recognition task as a model of memory deficit.

摘要

血清素 5-HT 受体被认为是增强认知的有前途的治疗靶点，尽管需要开发新的拮抗剂来验证这些分子作为治疗阿尔茨海默病和其他与记忆缺陷相关的病理学的药物类别。作为我们针对 5-HT 受体的努力的一部分，已经设计和合成了新的苯并咪唑基化合物。定点突变和同源模型表明，本文鉴定的新型 5-HT 受体拮抗剂类中的氯原子与跨膜结构域 4 中一个骨架羰基之间的卤键相互作用的重要性。5-HT 受体拮抗剂 7 的体外药理学特性表明，它对包括 5-HT 亚型和 hERG 通道在内的一系列受体具有高亲和力和选择性，这表明没有重大心脏问题。化合物 7 在新颖物体识别任务中表现出体内认知活性（1mg/kg，ip），作为记忆缺陷的模型。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1031/5259792/f2a723d52118/srep41293-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1031/5259792/a0021a8cf8ca/srep41293-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1031/5259792/2210a9bc817f/srep41293-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1031/5259792/e2989387c03d/srep41293-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1031/5259792/64be0dd38354/srep41293-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1031/5259792/721cc6c1fd09/srep41293-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1031/5259792/f2a723d52118/srep41293-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1031/5259792/a0021a8cf8ca/srep41293-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1031/5259792/2210a9bc817f/srep41293-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1031/5259792/e2989387c03d/srep41293-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1031/5259792/64be0dd38354/srep41293-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1031/5259792/721cc6c1fd09/srep41293-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1031/5259792/f2a723d52118/srep41293-f6.jpg

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