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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References
Schram, M., Thomas, G., Towart, R. and Franckowiak, G., Nature (Lond.), 303 (1983) 535.
Janis, R.A., Rampe, D., Sarmiento, J.G. and Triggle, D.J., Biochem. Biophys. Res. Commun. 121 (1984) 317.
Janis, R.A., Silver, P. and Triggle, D.J., Adv. Drug Res., 16 (1987) 309.
Triggle, D.J., Langs, D.A. and Janis, R.A., Med. Res. Rev. 9 (1989) 123.
Loev, B., Goodman, M.M., Snader, K.M., Tedeschi, R. and Macko, E., J. Med. Chem. 17 (1974) 956.
Rodenkirchen, R., Bayer, R., Steiner, R., Bossert, E., Meyer, H. and Möller, E., Naunyn-Schmied. Arch. Pharmacol., 310 (1979) 69.
Rodenkirchen, R., Bayer, R. and Mannhold, R., Prog. Pharmacol., 5 (1982) 9.
Triggle, A.M., Shefter, E. and Triggle, D.J., J. Med. Chem., 23 (1980) 1442.
Fossheim, R., Svarteng, K., Mostad, A., Rømming, C., Shefter, E. and Triggle, D.J., J. Med. Chem., 25 (1982) 126.
Coburn, R.A., Wierzba, M., Suto, M.J., Solo, A.J., Triggle, A.M. and Triggle, D.J., J. Med. Chem. 31 (1988) 2103.
Rampe, D. and Triggle, D.J., Trends Pharmacol. Sci., 7 (1987) 461.
Franckowiak, G., Bechem, M., Schram, M. and Thomas, G., Eur. J. Pharmacol., 114 (1985) 223.
Wei, X.Y., Luchowski, E.M., Rutledge, A., Su, C.M. and Triggle, D.J., J. Pharmacol. Exp. Therap., 239 (1986) 144.
Hof, P.R., Rüegg, U.T., Hof, A. and Vogel, A., J. Cardiovasc. Pharmacol. 7 (1985) 689
Gjörstrup, P., Hårding, H., Isaksson, R. and Westerlund, C., Eur. J. Pharmacol., 122 (1986) 357.
Fossheim, R., Joslyn, A., Solo, A.J., Luchowski, E., Rutledge, A. and Triggle, D.J., J. Med. Chem., 31 (1988) 300.
Langs, D.A. and Triggle, D.J., Mol. Pharmacol., 27 (1985) 544.
Fossheim, R., Acta Chem. Scand., B41 (1987) 581.
Kwon, Y.W., Franckowiak, G., Langs, D.A., Hawthorn, M., Joslyn, A. and Triggle, D.J., Naunyn-Schmied. Arch. Pharmacol., 339 (1989) 19.
Enraf-Nonius, Structure Determination Package, Enraf-Nonius, Delft, 1979.
Stout, G.H. and Jensen, L.H., X-ray Structure Determination, Macmillan, New York, 1968, p. 457.
Langs, D.A., Strong, P.D. and Triggle, D.J., J. Comput.-Aided Mol. Design, 4 (1990) 215.
Tanabe, T., Takeshima, H., Mikami, A., Flockerzi, V., Takahashi, H., Kangawa, K., Kojima, M., Matsuo, H., Hirose, T. and Numa, S., Nature (Lond.), 328 (1987) 313.
Mahmoudian, M. and Richards, W.G., J. Chem. Soc. Commun., (1986) 739.
Rovnyak, G., Andersen, N., Gougoutas, J., Hedberg, A., Kimball, S.D., Malley, M., Moreland, S., Porubcan, M. and Pubzianowski, A., J. Med. Chem., 31 (1988) 936.
Catterall, W.A., Science, 242 (1988) 50.
Guy, H.R. and Seetharamulu, P., Proc. Natl. Acad. Sci. USA, 83 (1986) 508.
Greenblatt, R.E., Blatt, Y. and Montal, M., FEBS Lett., 193 (1985) 125.
Höltje, H.-D. and Marrer, S., J. Comput.-Aided Mol. Design, 1 (1987) 23.
Höltje, H.-D. and Marrer, S., Quant. Struct.-Act. Relat., 7 (1988) 174.
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Langs, D.A., Kwon, Y.W., Strong, P.D. et al. Molecular level model for the agonist/antagonist selectivity of the 1,4-dihydropyridine calcium channel receptor. J Computer-Aided Mol Des 5, 95–106 (1991). https://doi.org/10.1007/BF00129749
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DOI: https://doi.org/10.1007/BF00129749