Positive allosteric modulators of the a7 nicotinic acetylcholine receptor: SAR investigation around PNU-120596

被引：0

作者：

Acker, Brad A. ^{[1
]}

Badescu, Valentina O. ^{[1
]}

Berkenpas, Mitchell B. ^{[1
]}

Groppi, Vincent E. ^{[1
]}

Hajos, Mihaly ^{[1
]}

Higdon, Nicole R. ^{[1
]}

Hurst, Raymond S. ^{[1
]}

Jacobsen, E. Jon ^{[1
]}

Margolis, Brandon J. ^{[1
]}

Mcwhorter, William W. ^{[1
]}

Myers, Jason K. ^{[1
]}

Piotrowski, David W. ^{[1
]}

Rogers, Bruce N. ^{[1
]}

Sarapa, Dusan ^{[1
]}

Vetman, Tatiana N. ^{[1
]}

Walker, Daniel P. ^{[1
]}

Wall, Theron M. ^{[1
]}

Wilhite, David M. ^{[1
]}

Wishka, Donn G. ^{[1
]}

Xu, Wenjian

Yates, Karen M.

机构：

[1] Pfizer Worldwide Res & Dev, Groton, CT 06340 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2023年 / 93卷

关键词：

nAChR; Allosteric; PAM; IN-VITRO; DISCOVERY; SYSTEM;

D O I：

10.1016/j.bmcl.2023.129433

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The & alpha;7 nicotinic acetylcholine receptor is a calcium permeable, ligand-gated ion channel that modulates synaptic transmission in the hippocampus, thalamus, and cerebral cortex. Previously disclosed work described PNU-120596 that acts as a powerful positive allosteric modulator of the & alpha;7 nicotinic acetylcholine receptor. The initial structure-activity relationships around PNU-120596 were gleaned from screening a large thiazole library. Independent systematic examination of the aryl and heteroaryl groups resulted in compounds with enhanced potency and improved physico-chemical properties culminating in the identification of 16 (PHA-758454). In the presence of acetylcholine, 16 enhanced evoked currents in rat hippocampal neurons. In a rat model of impaired sensory gating, treatment with 16 led to a reversal of the gating deficit in a dose-dependent manner. These results demonstrate that aryl heteroaryl ureas, like compound 16, may be useful tools for continued exploration of the unique biology of the & alpha;7 nicotinic acetylcholine receptor.

引用

页数：6

共 30 条

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