Properly substituted 1,4-dioxane nucleus favours the selective M3 muscarinic receptor activation.

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Piergentili A, Quaglia W, Del Bello F, Giannella M, Pigini M, Barocelli E, Bertoni S, Matucci R, Nesi M, Bruni B, Di Vaira M

Properly substituted 1,4-dioxane nucleus favours the selective M3 muscarinic receptor activation.

Bioorg Med Chem. 2009 Dec 15;17(24):8174-85. doi: 10.1016/j.bmc.2009.10.027. Epub 2009 Oct 20.

PubMed ID

19896386 [ View in PubMed

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Abstract

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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Carbamoylcholine	Muscarinic acetylcholine receptor M1	Ki (nM)	38018.94	N/A	N/A	Details
Carbamoylcholine	Muscarinic acetylcholine receptor M2	Ki (nM)	1230.27	N/A	N/A	Details
Carbamoylcholine	Muscarinic acetylcholine receptor M3	Ki (nM)	43651.58	N/A	N/A	Details
Carbamoylcholine	Muscarinic acetylcholine receptor M4	Ki (nM)	6309.57	N/A	N/A	Details