Document Detail

Highly chiral muscarinic ligands: the discovery of (2S,2'R,3'S,5'R)-1-methyl-2-(2-methyl-1,3-oxathiolan-5-yl)pyrrolidine 3-sulfoxide methyl iodide, a potent, functionally selective, M2 partial agonist.
MedLine Citation:
PMID:  16539379     Owner:  NLM     Status:  MEDLINE    
By further steric complication of previously studied highly chiral muscarinic agonists, we have obtained a small chiral library of enantiomeric and diasteromeric 1-methyl-2-(2-methyl-1,3-oxathiolan-5-yl)pyrrolidine 3-sulfoxides. Binding studies on cloned human muscarinic receptors expressed in CHO cells show that the introduction of a fourth stereogenic center gives undetectable affinity for hm1, hm3, hm4 and hm5 subtypes while leaving a quite modest affinity only for hm2 subtypes. However, functional studies on model M1-M4 muscarinic tissues have shown that three compounds of the series [(-)-5, (-)-7, (+)-8] are endowed with functional activity and behave as M2 selective partial agonists. Among them, compound (2S,2'R,3'S,5'R)-1-methyl-2-(2-methyl-1,3-oxathiolan-5-yl)pyrrolidine 3-sulfoxide methyl iodide [(+)-8] is particularly interesting, as it is a potent partial agonist on guinea pig atrium (force) (M2; pD2=7.65, alpha=0.41) while being a poor antagonist on M1, M3, and M4 model tissues (pKb<5).
Serena Scapecchi; Rosanna Matucci; Cristina Bellucci; Michela Buccioni; Silvia Dei; Luca Guandalini; Cecilia Martelli; Dina Manetti; Elisabetta Martini; Gabriella Marucci; Marta Nesi; Maria Novella Romanelli; Elisabetta Teodori; Fulvio Gualtieri
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Publication Detail:
Type:  In Vitro; Journal Article    
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  49     ISSN:  0022-2623     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2006 Mar 
Date Detail:
Created Date:  2006-03-16     Completed Date:  2006-04-28     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1925-31     Citation Subset:  IM    
Dipartimento di Scienze Farmaceutiche, Università di Firenze, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Italy.
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MeSH Terms
Atrial Function, Left / drug effects
CHO Cells
Cyclic S-Oxides / chemical synthesis*,  chemistry,  pharmacology
Guinea Pigs
Ileum / drug effects,  physiology
Lung / drug effects,  physiology
Muscle Contraction / drug effects
Muscle, Smooth / drug effects,  physiology
Pyrrolidines / chemical synthesis*,  chemistry,  pharmacology
Receptor, Muscarinic M2 / agonists*
Structure-Activity Relationship
Vas Deferens / drug effects,  physiology
Reg. No./Substance:
0/1-methyl-2-(2-methyl-1,3-oxathiolan-5-yl)pyrrolidine 3-sulfoxide methyl iodide; 0/Cyclic S-Oxides; 0/Ligands; 0/Pyrrolidines; 0/Receptor, Muscarinic M2

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