Accession Number : ADA263901

Title :   Computer-Assisted Determination of Minimum Energy Conformations. Vol 8. Structure Cardiovascular Activity of Detomidine Analogues.

Descriptive Note : Final rept. May-Jul 92,

Corporate Author : EDGEWOOD RESEARCH DEVELOPMENT AND ENGINEERING CENTER ABERDEEN PROVING GROUND MD

Personal Author(s) : Ashman, William P. ; Meehan, Brian S.

Report Date : MAR 1993

Pagination or Media Count : 71

Abstract : 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 compound/proposed adrenoceptor pharmacophore interaction provided additional features for analysis. Multiple regression analysis correlated each compound's octanol/water 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.

Descriptors :   *IMIDAZOLES, *CARDIOVASCULAR AGENTS, *PHARMACOKINETICS, BRADYCARDIA, CHEMISTRY, COEFFICIENTS, ELECTROSTATICS, HYPOTENSION, INTERACTIONS, MEAN, MOLECULES, NITROGEN, PARAMETERS, REGRESSION ANALYSIS, TACHYCARDIA, ARYL RADICALS, ALKYL RADICALS, BLOOD PRESSURE.

Subject Categories : Pharmacology

Distribution Statement : APPROVED FOR PUBLIC RELEASE