The long term objective of this proposal is to clarify the relationship between the molecular conformation and activities of an important group of cardiovascular drugs known as Ca2+ channel agents. Particular interest will be focused on the nifedipine family of 1,4-dihydropyridine drugs and concentrate on two areas: the determination of those features which distinguish agonists from antagonists, and the elucidation of those features which are responsible for selective potency in particular cardiovascular tissues. X-ray diffraction methods will be used to obtain molecular conformational data for a number of important compounds which are to include various aryl-substituted analogs of the lactone agonist, CGP 28 392, and tissue selective antagonists related to nitrendipine and nimodipine. Efforts will be extended to resolve racemic preparations of the various tissue selective analogs to provide enantiomeric samples which will be pharmacologically tested to determine the extent of chiral preference for selective activity. X-ray diffraction methods, employing anomalous scattering, will be used to determine the absolute configurations of those tissue selective analogs which show pronounced enantiomeric specificity. The MM2P molecular mechanics programs will be used to corroborate the crystallogaphically observed molecular conformations and resolve whether the non-observance of trans-trans di-esters is the result of a higher conformational energy or the inability of such conformers to hydrogen bond to their environment. The crystallographic conformational data will provide the basis to determine appropriate semi-empirical values for the parameters used in these calculations, especially those involving nitrogenous chemical functions. These proposed studies will augment the information which has become available in recent years regarding the chirality of the ligand-receptor interaction and the cycling of receptor-channel gating states. Crystallographic data obtained from the initial study period strongly suggest that there are a limited number of plausible ligand-receptor binding models which describe how these drugs may stabilize either the active open or inactive closed states of the Ca2+ channel. The proposed studies will provide answers which will further clarify the nature of this drug-receptor interaction by delineating the stereochemical characteristics required of these molecules to activate or inactivate the Ca2+ channel or enhance particular tissue selective response. This information will aid the design of more effective drugs.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL032303-04
Application #
3343659
Study Section
Biophysics and Biophysical Chemistry A Study Section (BBCA)
Project Start
1984-05-01
Project End
1990-04-30
Budget Start
1987-05-01
Budget End
1988-04-30
Support Year
4
Fiscal Year
1987
Total Cost
Indirect Cost
Name
Hauptman-Woodward Medical Research Institute
Department
Type
DUNS #
074025479
City
Buffalo
State
NY
Country
United States
Zip Code
14203
Langs, D A (1991) The direct determination of phase invariants provided by diffraction data measured at two different temperatures. Acta Crystallogr A 47 ( Pt 5):515-21
Langs, D A; Kwon, Y W; Strong, P D et al. (1991) Molecular level model for the agonist/antagonist selectivity of the 1,4-dihydropyridine calcium channel receptor. J Comput Aided Mol Des 5:95-106
Langs, D A; Smith, G D; Courseille, C et al. (1991) Monoclinic uncomplexed double-stranded, antiparallel, left-handed beta 5.6-helix (increases decreases beta 5.6) structure of gramicidin A: alternate patterns of helical association and deformation. Proc Natl Acad Sci U S A 88:5345-9
Langs, D A; Strong, P D; Triggle, D J (1990) Receptor model for the molecular basis of tissue selectivity of 1, 4-dihydropyridine calcium channel drugs. J Comput Aided Mol Des 4:215-30
Langs, D A (1989) Structure of the ion channel peptide antibiotic gramicidin A. Biopolymers 28:259-66
Duax, W L; Langs, D A; Pangborn, W A et al. (1989) Molecular conformation and ion transport of cyclic and linear ionophores. J Mol Graph 7:82-6, 99
Triggle, D J; Langs, D A; Janis, R A (1989) Ca2+ channel ligands: structure-function relationships of the 1,4-dihydropyridines. Med Res Rev 9:123-80
Langs, D A (1988) Three-dimensional structure at 0.86 A of the uncomplexed form of the transmembrane ion channel peptide gramicidin A. Science 241:188-91
Langs, D A; Han, F (1988) Direct methods: the identification of conditions which simplify the generation of inconsistent quadrupoles. Acta Crystallogr A 44 ( Pt 5):657-61
Han, F; Langs, D A (1988) Direct methods: the identification of space-group-specific inconsistent three-phase structure invariants. Acta Crystallogr A 44 ( Pt 4):563-6

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