Synthesis, absolute configuration and antimuscarinic activity of the enantiomers of [1-(2,2-diphenyl-[1,3]dioxolan-4-yl)-ethyl]-dimethyl-amine.
Methylation of the carbon atom C of compound 1, a potent and not selective muscarinic antagonist, was carried out. The resulting diastereomers were separated and the corresponding racemate further resolved to give four enantiomers, which were tested both as hydrogen oxalate and methiodide salts. The pharmacological results obtained at M1, M2 and M3 muscarinic receptor subtypes, show that methylation at C1, depending on the stereochemistry, increases antagonist potency, having thus the same effect of nitrogen quaternization. These results may well lead to the development of new potent antimuscarinic drugs lacking a cationic head.
Gulini
U
U
Dipartimento di Scienze Chimiche, Università degli Studi di Camerino, Italy.
Angeli
P
P
Marucci
G
G
Buccioni
M
M
Giardinà
D
D
Antolini
L
L
Franchini
S
S
Sorbi
C
C
Brasili
L
L
D000818:Animals; D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D004148:Dioxolanes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006168:Guinea Pigs; D006847:Hydrocarbons, Iodinated / Q000737:chemistry / Q000494:pharmacology; D007082:Ileum / Q000737:chemistry; D008297:Male; D008745:Methylation; D018727:Muscarinic Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009206:Myocardium / Q000737:chemistry; D010070:Oxalates / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D011817:Rabbits; D011976:Receptors, Muscarinic / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014649:Vas Deferens / Q000737:chemistry
C425227:(1-(2,2-diphenyl-(1,3)dioxolan-4-yl)-ethyl)-dimethyl-amine; D004148:Dioxolanes; D006847:Hydrocarbons, Iodinated; D018727:Muscarinic Antagonists; D010070:Oxalates; D011976:Receptors, Muscarinic; C014055:methyl iodide