Improving the Nicotinic Pharmacophore with a Series of (Isoxazole)methylene-1-azacyclic Compounds: Synthesis, Structure−Activity Relationship, and Molecular Modeling
| Autor: | Birgitte V. Christensen, Janne Ejrnæs Tønder, Ingrid Pettersson, Mikael Begtrup, John Bondo Hansen, Ulrich Ehrbar, Preben H. Olesen, Karin Rimvall |
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| Rok vydání: | 1999 |
| Předmět: |
Male
Models Molecular Nicotine Quinuclidines Chemical Phenomena Molecular model Nitrogen Stereochemistry Static Electricity Molecular Conformation Receptors Nicotinic Chemical synthesis Structure-Activity Relationship chemistry.chemical_compound Drug Discovery Muscarinic acetylcholine receptor medicine Animals Structure–activity relationship Rats Wistar Isoxazole Cerebral Cortex Molecular Structure Chemistry Physical Chemistry Hydrogen Bonding Isoxazoles Receptors Muscarinic Rats Nicotinic agonist Epibatidine Thermodynamics Molecular Medicine Pharmacophore medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 42:4970-4980 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | A series of (isoxazole)methylene-1-azacyclic compounds was prepared. The compounds were tested for affinity to central nicotinic acetylcholine receptors (nAChRs) and central muscarinic receptors. The compounds covered a broad range of affinities for the nAChRs (IC(50) = 0.32 to >1000 nM), with selectivities for the nAChRs over the muscarinic receptors in the range of 3-183. The high-affinity compound (Z)-26 (3-(4-methyl-5-isoxazolyl)methylene-1-azabicyclo[2.2. 2]octane, IC(50) = 3.2 nM) having only one energy minimum was used as the reference structure in a computational study. This ligand has enabled definition of an important distance parameter, and the existence of this parameter was supported by showing that other potent nicotinic ligands (for example, nicotine and epibatidine) fit the model. |
| Databáze: | OpenAIRE |
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