Potent muscarinic antagonists bearing 1,4-dioxane scaffold

Muscarinic receptor antagonists are used in the treatment of airway, bladder, and gastrointestinal smooth muscle disorders. In the treatment of overactive bladder (OAB) and OAB symptoms they are often associated with detrusor overactivity (DO) and exert their effects by inhibiting the binding of acetylcholine at muscarinic receptors M2 and M3 on detrusor smooth muscle cells and other structures within the bladder wall.1 (1,3-dioxolan-4-yl)-N,N,N-trimethylmethanaminium iodide nucleus has been used for many years as a scaffold for its ability to give potent muscarinic agonists or antagonists, depending on the size of the substituent in position 2 (methyl or bulkier group, respectively).2 The enlargement of the 1,3-dioxolane nucleus of 1 by inserting a methylene group between the 1-oxygen atom and the 2-carbon atom afforded the potent muscarinic agonist 2, which preferentially activated M2 and M3 subtypes.3 Therefore, to obtain a potent antagonist useful in the treatment of OAB, in the present study two phenyl rings have been inserted in position 6 of the 1,4-dioxane scaffold (compound 3). Moreover, since it is well known that muscarinic receptors display stereoselective requirements and the biological activity of muscarinic ligands is closely related to their stereochemistry,4 the racemate 3 has also been resolved into its two enantiomers via an oxazolidinone auxiliary mediated resolution. The absolute configuration of the two enantiomers has been determined through X-ray diffraction analysis of the dextrorotatory form. The pharmacological profile of racemate 3 and its two enantiomers was evaluated by receptor binding assays on Chinese hamster ovary (CHO) cells, expressing the five human muscarinic subtypes (hm1-hm5). From preliminary results compound 3 showed nM affinity values significantly similar to those of N-methylscopolamine at all muscarinic subtypes. The eutomer was the levorotatory form (S)-(−)-3 at all muscarinic M1-M5 subtypes, with eudismic ratios of 32, 12, 42, 102 and 63, respectively. References 1) Abrams, P.; Andersson, K.-E. BJU Int. 2007,100, 987-1006 2) a) Angeli, P. Farmaco 1995, 50, 565-77. b) Angeli, P. Farmaco 1998, 53, 1-21. 3) Piergentili, A.; Quaglia, W.; Giannella, M.; Del Bello, F.; Buccioni, M.; Nesi, M.; Matucci, R. Bioorg. Med. Chem. Lett. 2008, 18, 614-618. 4) Scapecchi, S.; Matucci, R.; Bellucci, C.; Buccioni, M.; Dei, S.; Guandalini, L.; Martelli, C.; Manetti, D.; Martini, E.; Marucci, G.; Nesi, M.; Romanelli, M. N.; Teodori, E.; Gualtieri, F. J. Med. Chem. 2006, 49, 1925-1931.