Investigations of amide bond variation and biaryl modification in analogues of α7 nAChR agonist SEN12333
| Autor: | Thao T. Olson, David E. Hibbs, John Tsanaktsidis, Teresa Xie, Andrew John Harvey, Michael Kassiou, Sue O'connor, Carolyn J. Coles, Corinne Beinat, Yingxian Xiao, Tristan A. Reekie |
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| Rok vydání: | 2014 |
| Předmět: |
Models
Molecular Agonist alpha7 Nicotinic Acetylcholine Receptor Pyridines medicine.drug_class Stereochemistry Isostere Morpholines Ring (chemistry) Structure-Activity Relationship chemistry.chemical_compound Amide Drug Discovery Pyridine medicine Humans Peptide bond Tetrazole Nicotinic Agonists Acetylcholine receptor Pharmacology Dose-Response Relationship Drug Molecular Structure Organic Chemistry General Medicine Amides chemistry |
| Zdroj: | European Journal of Medicinal Chemistry. 84:200-205 |
| ISSN: | 0223-5234 |
| Popis: | Several lines of experimental evidence support the involvement of the α7 nAChR in schizophrenia and Alzheimer's disease. Modulators of the α7 nAChR have been extensively reviewed for the treatment of the cognitive deficits associated with these pathologies. SEN12333 represents a novel α7 nAChR agonist chemotype with potential for reduced side effects but requiring further SAR exploration. The present work investigates the amide bond of SEN12333, specifically its connectivity and replacement with the tetrazole functionality, a known cis amide isostere. The results reveal the original amide bond connectivity of SEN12333 to be favorable for binding affinity and agonist activity at α7 nAChRs. The use of a tetrazole isostere completely abolishes affinity and functional activity and suggests that SEN12333 binds in a linear conformation. Results reported herein also suggest the pyridine nitrogen within the terminal aromatic ring of SEN12333 is not essential for binding affinity or functional activity. Further SAR investigations involving manipulation of other moieties contained within SEN12333 are warranted. |
| Databáze: | OpenAIRE |
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