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, R ) 0.41) while being a poor antagonist on M1, M3, and M4 model tissues (pKb < 5).

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 / Scapecchi, Serena; Matucci, Rosanna; Bellucci, Cristina; Buccioni, M.; Dei, Silvia; Guandalini, Luca; Martelli, Cecilia; Manetti, Dina; Martini, Elisabetta; Marucci, G.; Nesi, Marta; Romanelli, MARIA NOVELLA; Teodori, Elisabetta; Gualtieri, Fulvio. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - STAMPA. - 49:(2006), pp. 1925-1931. [10.1021/jm0510878]

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.

SCAPECCHI, SERENA;MATUCCI, ROSANNA;BELLUCCI, CRISTINA;DEI, SILVIA;GUANDALINI, LUCA;MARTELLI, CECILIA;MANETTI, DINA;MARTINI, ELISABETTA;NESI, MARTA;ROMANELLI, MARIA NOVELLA;TEODORI, ELISABETTA;GUALTIERI, FULVIO
2006

Abstract

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, R ) 0.41) while being a poor antagonist on M1, M3, and M4 model tissues (pKb < 5).
2006
49
1925
1931
Scapecchi, Serena; Matucci, Rosanna; Bellucci, Cristina; Buccioni, M.; Dei, Silvia; Guandalini, Luca; Martelli, Cecilia; Manetti, Dina; Martini, Elisabetta; Marucci, G.; Nesi, Marta; Romanelli, MARIA NOVELLA; Teodori, Elisabetta; Gualtieri, Fulvio
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/309135
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