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

Abstract

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)

A quantitation of stereoselectivity by the Free-Wilson method

“…They also reported that it was not possible, on the basis of the eudismic analysis results, to differentiate between muscarinic receptors. Lehmann 6 made his own analysis of these data confirming some of the findings of Gualtieri et al, and extending his study to quantify the criticality of the chiral centers. However, in both studies the analysis was limited by the small number of possible comparisons between stereoisomers.…”

“…Table 2 shows the results obtained from the FW/FB analyses for the affinity data of GPI, GPH, and RGB, and also those obtained using the affinity average at these three different tissues; the last analysis was made to compare our current results with those obtained by Lehmann 6 in his previous work (see below). The results report the calculated contribution to the affinity for the 11 possible fragments as well as the calculated affinity of the reference compound (µ).…”

“…This is despite the fact that they are conceptually different methods: the FW/FB assumes that the contribution of any substituent in any one position is constant and additive, while the EEA finds that the contributions are additive, but not constant since they increase with the affinity of the eutomer. 6 Also, in practice, the EEA works with subsets, while the FW/FB uses the complete set to estimate the contribution of the substituents and the criticality for the chiral centers. For this reason, the FW/FB method has the advantage that it takes into account the whole set so that its results are not based only on a few points.…”

“…Alternatively, Lehmann introduced eudismic analysis 4,5 and epimeric eudismic analysis (EEA) 6 as more suitable ways to quantify receptor stereoselectivity and the criticality of chiral centers, respectively. The usefulness of eudismic analysis and EEA has been shown in various publications (see references 4 and 5, and others cited therein).…”

Understanding topological symmetry: A heuristic approach to its determination

“…17 Also it could be of help during atom type assignment in molecular mechanics force fields especially for some complex symmetrical structures presenting difficulties for assessing equivalence or non-equivalence of some atoms like structure 18 on Table 6. On the other hand, the importance of chirality of drugs has been recognized for many years, and also, quantitative stereostructure-activity relationships QSSAR 18 or 3D-QSAR 19 using a fragment contribution approach for leading compounds search in drug design. For instance in drugs related to opioid receptors, such as methadone and the like, there are many compounds having chiral centers, and also topological SPs; so the method described in this work could be useful for detecting particular fragments or groups of atoms in those structures useful in topological discrimination considered in 3D-QSAR relationships.…”