Molecular level model for the agonist/antagonist selectivity of the 1,4-dihydropyridine calcium channel receptor.
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.
Langs
D A
DA
Department of Molecular Biophysics, Medical Foundation of Buffalo, Inc., NY 14203.
Kwon
Y W
YW
Strong
P D
PD
Triggle
D J
DJ
D002120:Calcium Channel Agonists / Q000737:chemistry*; D002121:Calcium Channel Blockers / Q000737:chemistry*; D015220:Calcium Channels / Q000737:chemistry; D003196:Computer Graphics; D015640:Ion Channel Gating; D008958:Models, Molecular; D015394:Molecular Structure; D011978:Receptors, Nicotinic / Q000737:chemistry*; D014961:X-Ray Diffraction
D002120:Calcium Channel Agonists; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D011978:Receptors, Nicotinic