J. Med. Chem. 1986,29, 1610-1615
1610
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Resolution, Absolute Configuration, and Cholinergic Enantioselectivity of ( )- and (-)-cis-2-Methyl-5-[(dimethylamino)methyl]-1,3-oxathiolaneMethiodide' Elisabetta Teodori,t Fulvio Gualtieri,*t Piero Angeli,* Livio Brasili,* Mario Giannella,* and Maria Piginit Dipartimento di Scienze Farmaceutiche, Uniuersitci di Firenze, 50121 Firenze, Italy, and Dipartimento di Chimica, Universitci di Camerino, 62032 Macerata, Italy. Received December 16, 1985 The potent cholinergic agonist (i)-cis-2-methyl-5-[(dimethylamino)methyl]-1,3-oxathiolane methiodide [ (+l] was resolved into enantiomeric forms. Their absolute configurations were established by a synthetic pathway that also allowed the synthesis of the corresponding diastereomeric (+)- and (-)-trans-2-methyl-5-[(dimethylamino)methyl]-l,3-oxathiolane methiodide [(+)- and (-)-lo]. Compound (+)-l,which is the most potent of the four isomers, showed the same absolute configuration as L-(+)-muscarineand (+)-cis-dioxolane. The four isomers were tested on guinea pig ileum and frog rectus abdominis, and their muscarinic and nicotinic potency (EPMR) and selectivity were determined. The relationships between stereoisomerism and potency are discussed. Enantiomers of muscarinic receptor agonists and antagonists demonstrate pharmacological enantioselectivity; this fact, coupled with structure-activity relationship studies (SAR), has provided much useful information on the molecular requirements of the recognition site of the muscarinic receptor and on its mode of interaction with specific ligands, leading t o the proposal of some models of the receptor binding ~ i t e . ~ - ~ In order to further such enantiomeric probing of the muscarinic receptor we decided to study the enantioselectivity of the two enantiomers of oxathiolane (1). In fact, c
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