Positive Allosteric Modulators of the α7 Nicotinic Acetylcholine Receptor: SAR Investigation Around PNU-120596
The α7 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 α7 nicotinic ac...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2023-09, Vol.93, p.129433-129433, Article 129433 |
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| creator | Acker, Brad A Badescu, Valentina O Berkenpas, Mitchell B Groppi, Vincent E Hajós, Mihaly Higdon, Nicole R Hurst, Raymond S Jon Jacobsen, E Margolis, Brandon J McWhorter, William W Myers, Jason K Piotrowski, David W Rogers, Bruce N Sarapa, Dusan Vetman, Tatiana N Walker, Daniel P Wall, Theron M Wilhite, David M Wishka, Donn G Xu, Wenjian Yates, Karen M |
| description | The α7 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 α7 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 α7 nicotinic acetylcholine receptor. |
| doi_str_mv | 10.1016/j.bmcl.2023.129433 |
| format | Article |
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| title | Positive Allosteric Modulators of the α7 Nicotinic Acetylcholine Receptor: SAR Investigation Around PNU-120596 |
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