Receptor model for the molecular basis of tissue selectivity of 1, 4-dihydropyridine calcium channel drugs.
Our analysis of the solid state conformations of nifedipine [dimethyl 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinecarboxylate ] and its 1,4-dihydropyridine (1,4-DHP) analogues produced a cartoon description of the important interactions between these drugs and their voltage-dependent calcium channel receptor. In the present study a molecular-level detailed model of the 1,4-DHP receptor binding site has been built from the published amino acid sequence of the alpha 1 subunit of the voltage-dependent calcium channel isolated from rabbit skeletal muscle transverse tubule membranes. The voltage-sensing component of the channel described in this work differs from other reported for the homologous sodium channel in that it incorporates a water structure and a staggered, rather than eclipsed, hydrogen bonded S4 helix conformation. The major recognition surfaces of the receptor lie in helical grooves on the S4 or voltage-sensing alpha-helix that is positioned in the center of the bundle of transmembrane helices that define each of the four calcium channel domains. Multiple binding clefts defined by Arg-X-X-Arg-P-X-X-S 'reading frames' exist on the S4 strand. The tissue selectivity of nifedipine and its analogues may arise, in part, from conservative changes in the amino acid residues at the P and S positions of the reading frame that define the ester-binding regions of receptors from different tissues. The crystal structures of two tissue-selective nifedipine analogues, nimodipine [isopropyl (2-methoxyethyl) 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinecarboxylate ] and nitrendipine [ethyl methyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3, 5-pyridinecarboxylate] are reported. Nimodipine was observed to have an unusual ester side chain conformation that enhances the fit to the proposed ester-sensing region of the receptor.
Langs
D A
DA
Department of Molecular Biophysics, Medical Foundation of Buffalo, Inc., NY 14203.
Strong
P D
PD
Triggle
D J
DJ
D000595:Amino Acid Sequence; D001665:Binding Sites; D002121:Calcium Channel Blockers / Q000737:chemistry / Q000494:pharmacology*; D015220:Calcium Channels; D003198:Computer Simulation; D004095:Dihydropyridines / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D009543:Nifedipine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D011978:Receptors, Nicotinic / Q000737:chemistry / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014961:X-Ray Diffraction
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D004095:Dihydropyridines; D011978:Receptors, Nicotinic; C038806:1,4-dihydropyridine; D009543:Nifedipine