Affinity and Selectivity of the Optical Isomers of 3-Quinuclidinyl BenzAlate and Related Muscarinic Antagonists

Article abstract of DOI:10.1021/jm00402a035

All the optical isomers of the muscarinic antagonists 3-(1-azabicyclo<2.2.2>octyl) α-hydroxy-α,α-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) α-hydroxy-α-phenylpropionate (3-quinuclidinyl atrolactate, QNA, 3) were prepared and studied in binding and functional assays.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 anatagonists 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.