Properly substituted 1,4-dioxane nucleus favours the selective M3 muscarinic receptor activation.
Novel analogues of cis-N,N,N-trimethyl-(6-methyl-1,4-dioxan-2-yl)methanaminium iodide (2a) were synthesized by inserting methyl groups alternatively or simultaneously in positions 5 and 6 of the 1,4-dioxane nucleus in all combinations. Their biological profile was assessed by receptor binding assays at human muscarinic M(1)-M(5) receptors stably expressed in CHO cells and by functional studies performed on classical isolated organ preparations, namely, rabbit electrically stimulated vas deferens, and guinea pig electrically stimulated left atrium, ileum, and lung strips. The results showed that the simultaneous presence of one methyl group in both positions 5 and 6 with a trans stereochemical relationship with each other (diastereomers 4 and 5) or the geminal dimethylation in position 6 (compound 8) favour the selective activation of M(3) receptors. Compounds 4, 5, and 8 might be valuable tools in the characterization of the M(3) receptor, as well as provide useful information for the design and development of novel selective M(3) antagonists.
Piergentili
Alessandro
A
Dipartimento di Scienze Chimiche, Università di Camerino, Via S Agostino 1, 62032 Camerino, Italy. alessandro.piergentili@unicam.it
Quaglia
Wilma
W
Del Bello
Fabio
F
Giannella
Mario
M
Pigini
Maria
M
Barocelli
Elisabetta
E
Bertoni
Simona
S
Matucci
Rosanna
R
Nesi
Marta
M
Bruni
Bruno
B
Di Vaira
Massimo
M
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus / Q000378:metabolism; D004146:Dioxanes / Q000494:pharmacology*; D006325:Heart Atria / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008297:Male; D043587:Receptor, Muscarinic M3 / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship
D004146:Dioxanes; D043587:Receptor, Muscarinic M3; C025223:1,4-dioxane