Quantitative correlations and reexamination of the importance of hydrophobic and steric factors in anticholinergic drug receptor interactions.
The pA2 (or log K) values at the muscarinic cholinergic receptor of the guinea pig ileum for a series of 1,3-dioxolanes have been correlated with the hydrophobic constant pi and pi 2. A correlation coefficient of 0.97 and standard deviation of 0.30 were obtained with 16 of the 18 compounds (P less than 0.05). A series of 17 analogues of amino esters of alpha-methyl tropic acid and alpha-substituted phenyl acetic acids, which were tested in the isolated rat ileal muscle, was analyzed, with a correlation coefficient of 0.92 and a standard deviation of 0.25 (P less than 0.05). Based on these results, the role of hydrophobic forces in the drug receptor interactions of muscarinic cholinergic receptors was analyzed. Optimum values for the physicochemical parameters were determined and their use in enhancing potency was suggested.
Division of Biomedicinal Chemistry, School of Pharmacy, University of Southern California, Los Angeles 90033.
S
S
Banerjee
E J
EJ
Lien
D000818:Animals; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008968:Molecular Conformation; D010276:Parasympatholytics / Q000494:pharmacology*; D011955:Receptors, Drug / Q000187:drug effects*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D010276:Parasympatholytics; D011955:Receptors, Drug