Affinity and selectivity of the optical isomers of 3-quinuclidinyl benzilate and related muscarinic antagonists

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Abstract
All of the optical isomers of the muscarinic antagonists 3-(1-azabicyclo[2.2.2]octyl) .alpha.-hydroxy-.alpha.,.alpha.-diphenylacetate (3-quinuclidinyl benzilate, QNB, 1), 3-(1-azabicyclo[2.2.2]octyl) xanthene-9-carboxylate (3-quinuclidinyl xanthene-9-carboxylate, QNX, 2), and 3-(1-azabicyclo[2.2.2]octyl) .alpha.-hydroxy-.alpha.-phenylpropionate (3-quinuclidinyl atrolactate, QNA, 3) were prepared and studied in binding and functional assays in rats. In all instances the esters of (R)-1-azabicyclo[2.2.2]octan-3-ol (3-quinuclidinol) had greater affinity for the M1 and M2 subpopulations of muscarinic acetylcholine receptors (M-AChRs) than did their S counterparts. The enantiomers of QNB (1), QNX (2), and QNA (3) in which the alcoholic portion of the muscarinic antagonists had the S absolute stereochemistry were more selective for the M1-AChRs. This selectivity was modulated by the nature and, in the case of QNA, the chirality of the acid portion. The most potent isomer in the series was (R)-QNB. In the QNA series the diastereoisomer with the absolute R configuration of the alcohol (a) and the R configuration of the acid (b) was the most potent in both binding and functional assays whereas (Sa,Rb)-QNA was the most selective for the M1 subtype of M-AChRs. In fact, the latter diastereomer was as potent and selective as pirenzepine for M1-AChRs.

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