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.
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).
Scapecchi
Serena
S
Dipartimento di Scienze Farmaceutiche, Università di Firenze, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Italy. serena.scapecchi@unifi.it
Matucci
Rosanna
R
Bellucci
Cristina
C
Buccioni
Michela
M
Dei
Silvia
S
Guandalini
Luca
L
Martelli
Cecilia
C
Manetti
Dina
D
Martini
Elisabetta
E
Marucci
Gabriella
G
Nesi
Marta
M
Romanelli
Maria Novella
MN
Teodori
Elisabetta
E
Gualtieri
Fulvio
F
D000818:Animals; D016279:Atrial Function, Left / Q000187:drug effects; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D003499:Cyclic S-Oxides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006168:Guinea Pigs; D006801:Humans; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D008024:Ligands; D008168:Lung / Q000187:drug effects / Q000502:physiology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011817:Rabbits; D043585:Receptor, Muscarinic M2 / Q000819:agonists*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014649:Vas Deferens / Q000187:drug effects / Q000502:physiology
C509859:1-methyl-2-(2-methyl-1,3-oxathiolan-5-yl)pyrrolidine 3-sulfoxide methyl iodide; D003499:Cyclic S-Oxides; D008024:Ligands; D011759:Pyrrolidines; D043585:Receptor, Muscarinic M2