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 M1–M5 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 M3 receptors. Compounds 4, 5, and 8 might be valuable tools in the characterization of the M3 receptor, as well as provide useful information for the design and development of novel selective M3 antagonists.

The novel ligands 4, 5, and 8 selectively activate M3 muscarinic receptors.Figure optionsDownload as PowerPoint slide