Studies Directed toward Ascertaining the Active Conformation of 1,4-Dihydropyridine Calcium Entry Blockers

George Rovnyak, S. David Kimball, Michael Porubcan, Jack Gougoutas, Mary Malley, Andrew Pudzianowsk, Anders Hedberg, Suzanne Moreland, Niels Andersen

Research output: Contribution to journalArticle

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Abstract

A series of unsymmetrically substituted 4-phenyl-1,4-dihydropyridine calcium entry blockers were investigated for their ability to relax potassium-contracted rabbit aortic smooth muscle and to competitively displace [3H] nitrendipine from its specific binding sites on guinea pig myocardial membranes in order to delineate the pharmacologically active conformer with respect to the position of the aromatic substituent (synperiplanar or antiperiplanar). The data show that the 1,4-dihydropyridine receptor distinguishes between 2ˊ,3ˊ-disubstituted phenyldihydropyridines and 2ˊ,5ˊ-disubstituted analogues as measured by changes of vasodilation and receptor affinity in vitro. The IC50 values for vasorelaxation by the analogues presented here correlate best with the Kd values for binding to the predominant receptor of two coexisting dihydropyridine binding sites in the guinea pig myocardium. We report the first observation of an antiperiplanar orientation of an o-phenyl substituent in the X-ray structure of 2-chlorophenyl analogue 3. Using nuclear Overhauser enhancement, we have developed a method that also demonstrates that an ortho (chloro or nitro) substituent on the phenyl ring does not preclude the presence of either synperiplanar or antiperiplanar phenyl rotamer in solution. These experimental findings contrast with the accepted belief that o-phenyl substituents essentially force these 1,4-dihydropyridines into the synperiplanar conformation exclusively.

Original languageEnglish (US)
Pages (from-to)936-944
Number of pages9
JournalJournal of medicinal chemistry
Volume31
Issue number5
DOIs
StatePublished - May 1 1988
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

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    Rovnyak, G., David Kimball, S., Porubcan, M., Gougoutas, J., Malley, M., Pudzianowsk, A., Hedberg, A., Moreland, S., & Andersen, N. (1988). Studies Directed toward Ascertaining the Active Conformation of 1,4-Dihydropyridine Calcium Entry Blockers. Journal of medicinal chemistry, 31(5), 936-944. https://doi.org/10.1021/jm00400a008