Molecular level model for the agonist/antagonist selectivity of the 1,4-dihydropyridine calcium channel receptor |
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Authors: | David A Langs Yong Wha Kwon Phyllis D Strong David J Triggle |
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Institution: | (1) Department of Molecular Biophysics, Medical Foundation of Buffalo, Inc., 14203 Buffalo, NY, U.S.A.;(2) Department of Biochemical Pharmacology, School of Pharmacy, State University of New York, Amherst Campus, 14260 Buffalo, NY, U.S.A. |
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Abstract: | Summary 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-carboxylate], 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-carboxylate] 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. |
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Keywords: | Calcium channel receptor Nifedipine activators Channel gating mechanism Crystal structures |
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