{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2023,10,23]],"date-time":"2023-10-23T13:07:47Z","timestamp":1698066467339},"reference-count":25,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2004,9,21]],"date-time":"2004-09-21T00:00:00Z","timestamp":1095724800000},"content-version":"vor","delay-in-days":5377,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Chirality"],"published-print":{"date-parts":[[1990,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Recently published data<jats:sup>1<\/jats:sup> on the aftinities of 14 pairs of chiral ligands, (1,3\u2010oxathiolanes) for muscarinic receptors in three different tissues were subjected to <jats:italic>eudismic analyses<\/jats:italic><\/jats:p><jats:p>The <jats:italic>enantiomeric<\/jats:italic> eudismic\u2010affinity correlations (EACs) found by Gualtieri et al.<jats:sup>1<\/jats:sup> 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\u2010oxathiolanes) 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<\/jats:p><jats:p>Furthermore, an <jats:italic>epimeric<\/jats:italic> EAC (EEAC) revealed additional important information for quantitative stereo\u2010structure\u2013activity 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 <jats:italic>X<\/jats:italic>\u2010intercept but with different slopes corresponding to epimerization at the different centers of chirality, indicating that these display <jats:italic>quantitative differences in their criticality<\/jats:italic> toward stereoselective recognition; (3) the remaining two antagonists of higher affinity fell on a separate line, again of unit slope.<\/jats:p><jats:p>The significance of these correlations is discussed in relation to receptor <jats:italic>speciation<\/jats:italic> and in regard to other stereoselectivity data available on muscarinic receptors<\/jats:p><jats:p>The quantitation of the <jats:italic>criticality<\/jats:italic> 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 <jats:italic>increases<\/jats:italic> with the overall affinity, a feature which might be applicable to all pharmaca, not just to those containing chiral molecules.<\/jats:p>","DOI":"10.1002\/chir.530020404","type":"journal-article","created":{"date-parts":[[2005,1,7]],"date-time":"2005-01-07T10:04:16Z","timestamp":1105092256000},"page":"211-218","source":"Crossref","is-referenced-by-count":7,"title":["Quantitation of the criticality of chiral centers toward stereoselective recognition: Epimeric eudismic analysis of 1,3\u2010oxathiolane muscarinic agonists and antagonists"],"prefix":"10.1002","volume":"2","author":[{"given":"Pedro A.","family":"Lehmann F.","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2004,9,21]]},"reference":[{"key":"e_1_2_1_2_2","doi-asserted-by":"crossref","unstructured":"Gualtieri F. Romanelli M.N. Teodori E.Eudismic analysis of a series of muscarinic ligands carrying a 1 3\u2010oxathiolane nucleus. Chirality 2:79\u201384 1990. I thank Prof. Gualtieri for sending me a preprint of this contribution which I received on January 3 1990.","DOI":"10.1002\/chir.530020204"},{"key":"e_1_2_1_2_3","first-page":"101","volume-title":"Progress in Drug Research","author":"Lehmann F., P.A.","year":"1976"},{"key":"e_1_2_1_2_4","first-page":"126","volume-title":"Progress in Drug Research","author":"Rodrigues de Miranda J.F.","year":"1976"},{"key":"e_1_2_1_3_2","first-page":"61","volume-title":"Mechanism of Drug Action","author":"Lehmann F.,P.A.","year":"1983"},{"key":"e_1_2_1_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/0165-6147(86)90353-6"},{"key":"e_1_2_1_5_2","first-page":"745","article-title":"Stereoselektivit\u00e4t bei bioaktiven Substanzen\u2010ein aktuelles Problemgebiet in Chemie und Biologie","volume":"43","author":"Schmidt K.","year":"1989","journal-title":"Osterr. Apotheker\u2010Zeitung."},{"key":"e_1_2_1_6_2","doi-asserted-by":"publisher","DOI":"10.1002\/qsar.19870060204"},{"key":"e_1_2_1_7_2","first-page":"17","article-title":"Affinity, efficacy and stereoselectivity of oxotremorine analogues for muscarinic receptors in the isolated guinea pig ileum","volume":"23","author":"Ringdahl B.","year":"1983","journal-title":"Mol. Pharmacol."},{"key":"e_1_2_1_8_2","unstructured":"Hern\u00e1ndez\u2010Gallegos Z. Lehmann F. P.A.A Free\u2010Wilson\/Fujita\u2010Ban analysis and prediction of the analgesic potency of some opioid narcotics (3\u2010hydroxy\u2010) and 3\u2010methoxy N\u2010alkylmorphinan\u20106\u2010ones. J. Med. Chem. in press."},{"key":"e_1_2_1_9_2","doi-asserted-by":"crossref","unstructured":"Already 34 years ago it was pointed out (Pfeiffer C.C. Optical isomerism and pharmacological action a generalization. Science 124:29\u201331 1956) that (last sentence to the caption of Fig. 1) \u201can intercept with the Y\u2010axis is not drawn since future work with more potent drugs may prove that the regression line approaches the Y\u2010axis asymptotically.\u201d The linearity of the plots in Figures 2 and 3 however do not support this conjecture.","DOI":"10.1126\/science.124.3210.29"},{"key":"e_1_2_1_10_2","first-page":"1","volume-title":"Receptors and Recognition","author":"Lehmann F., P.A.","year":"1978"},{"key":"e_1_2_1_11_2","doi-asserted-by":"publisher","DOI":"10.1098\/rstb.1970.0024"},{"key":"e_1_2_1_12_2","unstructured":"Lambrecht G. Mutschler E.Chirality as a tool for subclassification of receptors. Proc. 3d IUPAC\u2010IUPHAR Symposium on Innovative Approaches in Drug Research Noordwijkerhout NL 3\u20136 IX 85. In: Harms A.F. ed. Amsterdam: Elsevier 1986 353\u2013370."},{"key":"e_1_2_1_13_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm00130a007"},{"key":"e_1_2_1_14_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm00263a003"},{"key":"e_1_2_1_15_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm00273a010"},{"key":"e_1_2_1_16_2","first-page":"477","article-title":"The existence of stable enantiomers of telenzepine and their stereoselective interaction with muscarinic receptor subtypes","volume":"35","author":"Eveleigh P.","year":"1989","journal-title":"Mol. Pharmacol."},{"key":"e_1_2_1_17_2","unstructured":"Lehmann F. P.A. Estereoselectividad de receptores muscarinicos hacia el antagonista telenzepina\u2013una interpretaci\u00f3n por an\u00e1lisis eud\u00edsmico. Abstracts XIII Congreso Nacional de Farmacolog\u00eda P\u00e1tzcuaro Mich. p. 98 1989."},{"key":"e_1_2_1_18_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm00395a003"},{"key":"e_1_2_1_19_2","unstructured":"Waelbroeck M. Tastenoy M. Camus J. Feifel R. Mutschler E. Strohmann C. Tacke R. Lambrecht G. Christophe J.Stereoselectivity of the interaction of muscarinic antagonists with their receptors.Trends Pharmacol. Sci. Suppl.65\u201369 1989. I thank the authors for a preprint received 27 November 1989."},{"key":"e_1_2_1_20_2","doi-asserted-by":"publisher","DOI":"10.1002\/chir.530010212"},{"key":"e_1_2_1_21_2","unstructured":"Lambrecht G. Feifel R. Moser U. Wagner\u2010R\u00f6der M. Choo L.K. Camus J. Tastenoy M. Waelbroeck M. Strohmann C. Tacke R. Rodrigues de Miranda J.F. Christophe J. Mutschler E.Pharmacology of hexahydrodifenidol hexahydro\u2010sila\u2010difenidol and related selective muscarinic antagonists.Trends Pharmacol. Sci. Suppl.60\u201364 1989."},{"key":"e_1_2_1_22_2","unstructured":"It is interesting to note that for the procyclidine enantiomers binding at guinea pig ileal sites the observed EI was 2.58 (pEu = 8.04 pDis = 5.64) on going from an R\u2010configured carbon bearing phenyl and cyclohexyl substituents to its enantiomer. Using the equation for line B (Fig. 2) an EI of 2.69 is predicted; when more appropriately the regression equation for Gualtieri's ileal data1is used (EI = \u20107.278 + 1.227 pEu n = 6 r2= 0.987) the predicted EI is 2.59 nearly identical with that measured."},{"key":"e_1_2_1_23_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm00378a021"},{"key":"e_1_2_1_23_3","doi-asserted-by":"publisher","DOI":"10.1016\/0165-6147(86)90292-0"}],"container-title":["Chirality"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fchir.530020404","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/chir.530020404","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,22]],"date-time":"2023-10-22T17:09:17Z","timestamp":1697994557000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/chir.530020404"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1990,1]]},"references-count":25,"journal-issue":{"issue":"4","published-print":{"date-parts":[[1990,1]]}},"alternative-id":["10.1002\/chir.530020404"],"URL":"https:\/\/doi.org\/10.1002\/chir.530020404","archive":["Portico"],"relation":{},"ISSN":["0899-0042","1520-636X"],"issn-type":[{"value":"0899-0042","type":"print"},{"value":"1520-636X","type":"electronic"}],"subject":[],"published":{"date-parts":[[1990,1]]}}}