THE LIPOSOME AS A MODEL MEMBRANE IN CORRELATIONS OF PARTITIONING WITH ALPHA-ADRENOCEPTOR AGONIST ACTIVITIES

The apparent partition coefficients of a group of imidazoline α-adrenoceptor agonists in liposome/buffer systems (K′m) and in the n-octanol/buffer system (P′) have been compared in quantitative structure–activity relationships (QSAR) employing biological activities and receptor binding affinities. A parabolic relationship between log K′m and log P′ was found, and log K′m was greater than log P′ for all liposome compositions. In liposomes, log K′m decreased in the order, negatively charged > neutral > positively charged. Overall, hyper- and hypotensive activities of these drugs correlated better with log K′m than with log P′; however, poor correlations were obtained between partition coefficients and in vitro binding affinities. Linear correlations of log K′m with hypotensive activities were obtained with negatively charged liposomes, whereas correlations with hypertensive activities were obtained using positively charged liposomes. Multiple regressions of biological activities with binding affinities showed positive correlations with hypotensive but not hypertensive activities with or without the inclusion of log K′m or log P′. Thus, the liposome represents a more selective model membrane system than a bulk oil phase for predicting the biological activities of imidazoline α-adrenoceptor agonists. © 1990, Plenum Publishing Corporation. All rights reserved.