SITE SPECIFIC CALCIUM BLOCKERS: STRUCTURAL REQUIREMENTS

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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.