Molecular level model for the agonist/antagonist selectivity of the 1,4-dihydropyridine calcium channel receptor
| Autor: | Phyllis D. Strong, Yong Wha Kwon, David A. Langs, David J. Triggle |
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| Rok vydání: | 1991 |
| Předmět: |
Models
Molecular Molecular Structure Chemistry Stereochemistry Activator (genetics) Hydrogen bond Agonist-antagonist Calcium channel Dihydropyridine Antagonist Receptors Nicotinic Calcium Channel Blockers Computer Science Applications Calcium Channel Agonists chemistry.chemical_compound X-Ray Diffraction Drug Discovery Computer Graphics medicine Calcium Channels Carboxylate Physical and Theoretical Chemistry Binding site Ion Channel Gating medicine.drug |
| Zdroj: | Journal of Computer-Aided Molecular Design. 5:95-106 |
| ISSN: | 1573-4951 0920-654X |
| DOI: | 10.1007/bf00129749 |
| Popis: | Crystal structures of the 1,4-dihydropyridine (1,4-DHP) calcium channel activators Bay K 8643 [methyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(3-nitrophenyl)-pyridine-5-carboxy lat e], Bay O 8495 [methyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(3-trifluoromethylphenyl)-pyridine-5- carboxylate], and Bay O 9507 [methyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(4-nitrophenyl)-pyridine-5-carboxy lat e] were determined. The conformations of the 1,4-DHP rings of these activator analogues of Bay K 8644 [methyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)-pyridine-5- carboxylate] do not suggest that their activator properties are as strongly correlated with the degree of 1,4-DHP ring flattening as was indicated for members of the corresponding antagonist series. The solid state hydrogen bonding of the N(1)-H groups of the activators is not, unlike that of their antagonist counterparts, to acceptors that are directly in line with the donor. Rather, acceptor groups are positioned within +/- 60 degrees of the N(1)-H bond in the vertical plane of the 1,4-DHP ring. Previously determined structure-activity relationships have indicated the importance of this N(1)-H group to the activity of the 1,4-DHP antagonists. Based on these observations, a model is advanced to describe the 1,4-DHP binding site of the voltage-gated Ca2+ channel and its ability to accommodate both antagonist and activator ligands. |
| Databáze: | OpenAIRE |
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