Quantitation of the criticality of chiral centers toward stereoselective recognition: epimeric eudismic analysis of 1,3-oxathiolane muscarinic agonists and antagonists.
Recently published data on the affinities of 14 pairs of chiral ligands, (1,3-oxathiolanes) for muscarinic receptors in three different tissues were subjected to eudismic analyses. The enantiomeric eudismic-affinity correlations (EACs) found by Gualtieri et al. were confirmed and extended to the submolecular level: (1) regressions of the eudismic index (log affinity ratio; EI) against eutomer potency of the average affinities were highly significant, indicating that the binding sites in all three tissues are identical; (2) for the five agonists the EAC was shifted to lower affinities and had a small slope (EAQ), in agreement with previous observations in other systems; (3) of the nine antagonists, six gave an excellent regression with unit slope, practically superimposable on that previously obtained for 10 structurally different oxotremorine derivatives, while two others (1,3-oxathiolanes) could be plotted on a separate line with the same EAQ, but shifted to higher affinities; (4) the aberrant low EI of the last antagonist could be explained in terms of its structure. Furthermore, an epimeric EAC (EEAC) revealed additional important information for quantitative stereo-structure-activity relationships (QSSAR): the 25 possible epimeric comparisons were found to group into 6 different EACs in accord with differences in their structure: (1) the agonists fell on three separate lines of nearly identical (unitary) slope, which grouped cleanly in terms of the center of epimerization (positions 2, 3, and 5); (2) the antagonists of lower affinity fell on three lines with a common X-intercept but with different slopes corresponding to epimerization at the different centers of chirality, indicating that these display quantitative differences in their criticality toward stereoselective recognition; (3) the remaining two antagonists of higher affinity fell on a separate line, again of unit slope.(ABSTRACT TRUNCATED AT 250 WORDS)
Lehmann
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PA
Departamento de Farmacología y Toxicología, Instituto Politécnico Nacional, México D.F.
D000818:Animals; D006571:Heterocyclic Compounds / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D007700:Kinetics; D008968:Molecular Conformation; D010277:Parasympathomimetics / Q000737:chemistry* / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism*; D012044:Regression Analysis; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D006571:Heterocyclic Compounds; D010277:Parasympathomimetics; D011976:Receptors, Muscarinic