Comprehensive Analysis of Quantitative Structure‐Activity Relationships of Catecholamine‐Uptake Inhibitors
Yukimasa Terada, Tatsuya Tomita, Yoshiharu Inami · Quantitative Structure-Activity Relationships · 1991
Abstract Quantitative Structure‐Activity Relationships (QSAR) of inhibitors of dopamine (DA)‐ and norepinephrine (NE)‐uptake have been analyzed quantitatively. Previously, we reported that several series of congeners are susceptible to similar substituent effects, and these structurally diverse compounds interact with common receptor points by the hydrophobic interaction of a phenyl group and the hydrogen bonding of a nitrogen atom. In this report, we extended this concept to derive an equation that quantitatively interprets the activity of 113 compounds comprising 6 skeletal groups. Excellent QSAR equations were obtained in which all parameters used were physicochemically significant. Of the parameters adopted therein, the root mean square (rms) of the distances between corresponding pharmacophore was an especially valuable parameter to compare the activity of the structurally diverse compounds. On the other hand, a substituent existing in a specific region of the inhibitor molecule causes steric hindrance with the receptor and interferes with an effective binding of the inhibitor. Lastly, it was concluded that a degree of correspondence of proper pharmacophore to the receptor points, as well as the volume of that specific region, principally determines the binding ability of that congener, and the substituent effect of each compound is added to that fundamental affinity.