Quantitation of the criticality of chiral centers toward stereoselective recognition: Epimeric eudismic analysis of 1,3‐oxathiolane muscarinic agonists and antagonists

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Abstract
Recently published data1 on the aftinities of 14 pairs of chiral ligands, (1,3‐oxathiolanes) for muscarinic receptors in three different tissues were subjected to eudismic analysesThe enantiomeric eudismic‐affinity correlations (EACs) found by Gualtieri et al.1 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 structureFurthermore, 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.The significance of these correlations is discussed in relation to receptor speciation and in regard to other stereoselectivity data available on muscarinic receptorsThe quantitation of the criticality of different chiral centers, made possible here by the very high binding energies involved, should also be applicable to other stereoselective recognition processes (e.g., in enantioselective chromatography). Finally, a fundamental assumption of molecular pharmacology and QSAR, i.e., that a given structural feature always contributes a constant amount to the overall binding energy, is questioned in view of the above findings, which indicate that the contribution increases with the overall affinity, a feature which might be applicable to all pharmaca, not just to those containing chiral molecules.