Computer-Assisted Determination of Minimum Energy Conformations. Vol 8. Structure Cardiovascular Activity of Detomidine Analogues.
Final rept. May-Jul 92,
EDGEWOOD RESEARCH DEVELOPMENT AND ENGINEERING CENTER ABERDEEN PROVING GROUND MD
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A series of detomidine-like arylalkyl imidazoles and compounds known to be agonists at the alpha 2 adrenergic receptor are studied to identify structural, electrostatic, and physicochemical parameters related to various cardiovascular tachycardia, hypotension, bradycardia, mean arterial pressure activities. Semi-empirical PM3 quantum chemical calculations determined the lowest energy conformations and electrostatic parameters of each compound. A molecular modeling analysis for compoundproposed adrenoceptor pharmacophore interaction provided additional features for analysis. Multiple regression analysis correlated each compounds octanolwater partition coefficient the electrostatic environment around a specific nitrogen region of the module, geometric positions of compound functional groups in relationship to a proposed binding site on the adrenoceptor pharmacophore and the presence of specific compound functional groups with cardiovascular activity.