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2-苯-1-吡咯-3-甲酰胺作为开发具有认知增强活性的 5-HT 受体反向激动剂的新骨架。

2-Phenyl-1-pyrrole-3-carboxamide as a New Scaffold for Developing 5-HT Receptor Inverse Agonists with Cognition-Enhancing Activity.

机构信息

Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Str., 30-688 Kraków, Poland.

IBMM, Université de Montpellier, CNRS, ENSCM, 34095 Montpellier, France.

出版信息

ACS Chem Neurosci. 2021 Apr 7;12(7):1228-1240. doi: 10.1021/acschemneuro.1c00061. Epub 2021 Mar 11.

DOI:10.1021/acschemneuro.1c00061
PMID:33705101
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8041276/
Abstract

Serotonin type 6 receptor (5-HTR) has gained particular interest as a promising target for treating cognitive deficits, given the positive effects of its antagonists in a wide range of memory impairment paradigms. Herein, we report on degradation of the 1-pyrrolo[3,2-]quinoline scaffold to provide the 2-phenyl-1-pyrrole-3-carboxamide, which is devoid of canonical indole-like skeleton and retains recognition of 5-HTR. This modification has changed the compound's activity at 5-HTR-operated signaling pathways from neutral antagonism to inverse agonism. The study identified compound that behaves as an inverse agonist of the 5-HTR at the Gs and Cdk5 signaling pathways. Compound showed high selectivity and metabolic stability and was brain penetrant. Finally, reversed scopolamine-induced memory decline in the novel object recognition test and exhibited procognitive properties in the attentional set-shifting task in rats. In light of these findings, might be considered for further evaluation as a new cognition-enhancing agent, while 2-phenyl-1-pyrrole-3-carboxamide might be used as a template for designing 5-HTR inverse agonists.

摘要

5-羟色胺 6 型受体（5-HTR）作为一种有前途的治疗认知障碍的靶点引起了特别关注，因为其拮抗剂在广泛的记忆损伤模型中具有积极的效果。在此，我们报告了 1-吡咯并[3,2-]喹啉支架的降解，以提供缺乏典型吲哚样骨架但保留对 5-HTR 识别的 2-苯基-1-吡咯-3-甲酰胺。这种修饰改变了化合物在 5-HTR 操作的信号通路中的活性，从中性拮抗作用变为反向激动作用。该研究确定了化合物 ，它在 Gs 和 Cdk5 信号通路中作为 5-HTR 的反向激动剂。化合物 表现出高选择性和代谢稳定性，并且具有脑穿透性。最后， 逆转了东莨菪碱诱导的大鼠新物体识别测试中的记忆衰退，并在注意力转换任务中表现出认知促进作用。鉴于这些发现， 可能被认为是进一步评估作为一种新的认知增强剂，而 2-苯基-1-吡咯-3-甲酰胺可能被用作设计 5-HTR 反向激动剂的模板。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e21/8041276/3ed178148002/cn1c00061_0007.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e21/8041276/d16b50e7852d/cn1c00061_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e21/8041276/2b14789e34e5/cn1c00061_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e21/8041276/99126851935e/cn1c00061_0005.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e21/8041276/3ed178148002/cn1c00061_0007.jpg

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