The mechanism of drug interaction with and localization in cardiac and model membranes will be investigated at the molecular level utilizing neutron diffraction with stable isotopic deuteration of drug molecules, and x-ray diffraction with drug molecules containing an electron dense atom (e.g. sulfur, iodine, and mercury). The high lipid solubility of several calcium channel and beta blocking drugs suggests that the primary nonspecific site of interaction is the lipid bilayer component of biological membranes. The purified (light fraction) skeletal sarcoplasmic reticulum membrane and extracted lipids from a canine sarcolemmal preparation will be used as a model for studying nonspecific drug interaction since these membrane preparations do not contain protein receptors specific for these drugs. Nonspecific site of drug interaction will be examined for drug concentrations approximately equal to 10-6 M. A reconstituted receptor enriched membrane prepared from canine cardiac sarcolemma will be used in x-ray diffraction studies of specific drug interaction over a concentration range suitable for specific binding of the drug to the receptor as well as higher drug concentrations favoring nonspecific binding to non receptor and receptor enricched membranes in an attempt to define a structural model for drug interactions with membranes. Such determinations of the localization of these drug molecules in the lipid bilayer of biological membranes with and without specific receptors may provide insight into the mechanism by which these drug molecules """"""""locate"""""""" their specific protein receptor sites via the lipid bilayer component of these membranes. This approach can provide unique information as to how these drugs perturb the structure of the membrane, where they act in a specific and nonspecific fashion, and may provide a structural basis for elucidating their molecular mechanism of action. This last possibility offers prospects for the development of new drugs for clinical use that capitalize on structural aspects related to their desired actions while avoiding those structural features that can lead to detrimental side effects.
