Choi Y W, Rogers J A
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
Pharm Res. 1990 May;7(5):508-12. doi: 10.1023/a:1015820917453.
The apparent partition coefficients of a group of imidazoline alpha-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 greater than neutral greater than 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 alpha-adrenoceptor agonists.
在利用生物活性和受体结合亲和力的定量构效关系（QSAR）研究中，比较了一组咪唑啉α-肾上腺素能受体激动剂在脂质体/缓冲液系统（K'm）和正辛醇/缓冲液系统（P'）中的表观分配系数。发现log K'm与log P'之间呈抛物线关系，并且对于所有脂质体组成，log K'm均大于log P'。在脂质体中，log K'm按以下顺序降低：带负电荷的大于中性的大于带正电荷的。总体而言，这些药物的升压和降压活性与log K'm的相关性优于与log P'的相关性；然而，分配系数与体外结合亲和力之间的相关性较差。带负电荷的脂质体中log K'm与降压活性呈线性相关，而带正电荷的脂质体中log K'm与升压活性呈线性相关。生物活性与结合亲和力的多元回归显示，无论是否包含log K'm或log P'，与降压活性呈正相关，但与升压活性无关。因此，对于预测咪唑啉α-肾上腺素能受体激动剂的生物活性，脂质体比本体油相代表了一种更具选择性的模型膜系统。
