Binding Interactions of NS6740, a Silent Agonist of the α7 Nicotinic Acetylcholine Receptor
| Autor: | Dennis A. Dougherty, Catriona E. W. Blunt |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Pharmacology Agonist chemistry.chemical_classification Allosteric modulator medicine.drug_class Mutagenesis Alpha (ethology) Partial agonist Amino acid 03 medical and health sciences Nicotinic acetylcholine receptor 030104 developmental biology 0302 clinical medicine chemistry medicine Molecular Medicine Receptor 030217 neurology & neurosurgery |
| Zdroj: | Molecular Pharmacology. 96:212-218 |
| ISSN: | 1521-0111 0026-895X |
| Popis: | The α7 nicotinic acetylcholine receptor (nAChR) is a potential drug target for the treatment of a number of neurological and inflammatory disorders. Silent agonists are an emerging class of drugs that bind to the receptor but do not open the channel. Instead they shift the receptor to a desensitized state. Silent agonists may be able to target a subset of α7 nAChR mediated signaling processes. Here we use non-canonical amino acid mutagenesis to characterize the binding to α7 by the silent agonist NS6740. We find that like α7 agonists, NS6740 forms a cation-π interaction with Y115 (TyrA). We also showed that NS6740 makes a novel hydrogen bond to TyrA. This interaction is necessary for the silent agonist activity of NS6740; when the hydrogen bond is blocked silent agonist NS6740 converts to a conventional partial agonist and appreciably opens the channel in the absence of a positive allosteric modulator. SIGNIFICANCE STATEMENT Silent agonists represent and interesting new class of active compounds. Here we evaluate the binding of a silent agonist - NS6740 - to the &[alpha]7 nicotinic acetylcholine receptor. Among other things, we find a novel hydrogen bond that suggests strategies for developing new active compounds. |
| Databáze: | OpenAIRE |
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