Enantioselectivity of muscarinic antagonists. Isomeric 2-cyclohexyl-2-phenyl-5-[(dimethylamino)methyl]-1,3-oxathiolane 3-oxide methiodides.
The eight isomers of 2-cyclohexyl-2-phenyl-5-[(dimethylamino)methyl]-1, 3-oxathiolane 3-oxide methiodides were prepared and their absolute configurations were attributed by synthesis and by X-ray crystallography. The compounds were tested on guinea pig bladder, ileum, and heart and their antimuscarinic potency was evaluated and expressed as pA2. The absolute configuration of the most potent isomer [(+)-(2R,3R,5R)-7] is identical with that of the corresponding agonist [(2R,3R,5R)-c-2-methyl-r-5-[(dimethylamino)methyl]-1,3-oxathiolane t-e-oxide methiodide],3 which further supports our previous hypothesis that muscarinic agonists and antagonists of this series recognize a common binding site. While some of the racemates (3,4) show different enantioselectivity on the different tissues, the most potent and the most enantioselective one (7) does not discriminate between muscarinic receptors as it shows eudismic ratios of the same order for all tissues examined.
Romanelli
M N
MN
Dipartimento di Scienze Farmaceutiche, Firenze, Italy.
Gualtieri
F
F
Angeli
P
P
Picchio
M T
MT
D000818:Animals; D016275:Atrial Function; D003510:Cyclohexanes / Q000138:chemical synthesis* / Q000494:pharmacology; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D007536:Isomerism; D007537:Isometric Contraction / Q000187:drug effects; D008297:Male; D008968:Molecular Conformation; D015394:Molecular Structure; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology*; D009200:Myocardial Contraction / Q000187:drug effects*; D010276:Parasympatholytics / Q000138:chemical synthesis*; D013329:Structure-Activity Relationship; D001743:Urinary Bladder / Q000187:drug effects / Q000502:physiology
D003510:Cyclohexanes; D006571:Heterocyclic Compounds; D007202:Indicators and Reagents; D010276:Parasympatholytics