Molecular level model for the agonist/antagonist selectivity of the 1,4-dihydropyridine calcium channel receptor

SummaryCrystal 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.

[1]  W. Richards,et al.  A conformational distinction between dihydropyridine calcium agonists and antagonists , 1986 .

[2]  U. Ruegg,et al.  Stereoselectivity at the Calcium Channel: Opposite Action of the Enantiomers of a 1,4‐Dihydropyridine , 1985, Journal of cardiovascular pharmacology.

[3]  S. Moreland,et al.  Studies directed toward ascertaining the active conformation of 1,4-dihydropyridine calcium entry blockers. , 1988, Journal of medicinal chemistry.

[4]  W. Catterall,et al.  Structure and function of voltage-sensitive ion channels. , 1988, Science.

[5]  A M Triggle,et al.  Crystal structures of calcium channel antagonists: 2,6-dimethyl-3,5-dicarbomethoxy-4-[2-nitro-, 3-cyano-, 4-(dimethylamino)-, and 2,3,4,5,6-pentafluorophenyl]-1,4-dihydropyridine. , 1980, Journal of medicinal chemistry.

[6]  D. Langs,et al.  Ca2+ channel ligands: Structure‐function relationships of the 1,4‐dihydropyridines , 1989, Medicinal research reviews.

[7]  D J Triggle,et al.  Crystal structures and pharmacologic activities of 1,4-dihydropyridine calcium channel antagonists of the isobutyl methyl 2,6-dimethyl-4-(substituted phenyl)-1,4-dihydropyridine-3,5-dicarboxylate (nisoldipine) series. , 1988, Journal of medicinal chemistry.

[8]  D J Triggle,et al.  Pharmacologic and radioligand binding analysis of the actions of 1,4-dihydropyridine activator-antagonist pairs in smooth muscle. , 1986, The Journal of pharmacology and experimental therapeutics.

[9]  H. Guy,et al.  Molecular model of the action potential sodium channel. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[10]  David J. Triggle,et al.  Receptor model for the molecular basis of tissue selectivity of 1,4-dihydropyridine calcium channel drugs , 1990, J. Comput. Aided Mol. Des..

[11]  R. Greenblatt,et al.  The structure of the voltage‐sensitive sodium channel , 1985, FEBS letters.

[12]  D. Langs,et al.  Conformational features of calcium channel agonist and antagonist analogs of nifedipine. , 1984, Molecular pharmacology.

[13]  D. Triggle,et al.  Benzodiazepines and calcium channel function , 1986 .

[14]  D. Triggle,et al.  Drug action and cellular calcium regulation , 1987 .

[15]  K. Snader,et al.  Hantzsch-type dihydropyridine hypotensive agents , 1974 .

[16]  H. Höltje,et al.  Qualitative and quantitative structure-activity relationships for calcium channel modulating 1,4-dihydropyridine derivatives: a hypothetical molecular receptor model , 1988 .

[17]  V. Flockerzi,et al.  Primary structure of the receptor for calcium channel blockers from skeletal muscle , 1987, Nature.

[18]  A M Triggle,et al.  1,4-Dihydropyridine antagonist activities at the calcium channel: a quantitative structure-activity relationship approach. , 1988, Journal of medicinal chemistry.

[19]  Hans-Dieter Höltje,et al.  A molecular graphics study on structure-action relationships of calcium-antagonistic and agonistic 1,4-dihydropyridines , 1987, J. Comput. Aided Mol. Des..

[20]  R. Isaksson,et al.  The enantiomers of the dihydropyridine derivative H 160/51 show opposite effects of stimulation and inhibition. , 1986, European journal of pharmacology.

[21]  J. G. Sarmiento,et al.  Specific binding of a calcium channel activator, [3H]BAY k 8644, to membranes from cardiac muscle and brain. , 1984, Biochemical and biophysical research communications.

[22]  M. Bechem,et al.  The optical isomers of the 1,4-dihydropyridine BAY K 8644 show opposite effects on Ca channels. , 1985, European journal of pharmacology.

[23]  C. Romming,et al.  Crystal structures and pharmacological activity of calcium channel antagonists: 2,6-dimethyl-3,5-dicarbomethoxy-4-(unsubstituted, 2-methyl-, 4-methyl-, 3-nitro-, 4-nitro-, and 2,4-dinitrophenyl)-1,4-dihydropyridine. , 1982, Journal of medicinal chemistry.

[24]  M. Schramm,et al.  Novel dihydropyridines with positive inotropic action through activation of Ca2+ channels , 1983, Nature.

[25]  R. Fossheim Crystal structure of a 1,4-dihydropyridine with enantiomers showing opposite effects on calcium channels: structural features of calcium channel agonists and antagonists. , 1987, Acta chemica Scandinavica. Series B: Organic chemistry and biochemistry.