Novel muscarinic antagonists designed on the 1,4-dioxane scaffold

The five subtypes of muscarinic receptors (M1-M5) are widely distributed on multiple organs and tissues and are critical to the maintenance of central and peripheral cholinergic neurotrasmission. Smooth muscle expresses several muscarinic receptor subtypes, the most important being M2 and M3 subtypes from a functional point of view. Although the M2 muscarinic subtypes are predominant, the smaller population of M3 subtypes appears to be the most functionally important for treating various medical conditions associated with improper smooth muscle function, such as overactive bladder (OAB), chronic obstructive pulmonary disease (COPD), and pain-predominant irritable bowel syndrome (IBS). Due to the wide distribution of muscarinic receptors in the body, significant systemic exposure to muscarinic antagonists is associated with effects such as dry mouth, constipaton, mydriasis, urinary retention and tachycardia. Therefore, the discovery of novel muscarinic antagonists showing target organ selectivity would be very useful (1). The (1,4-dioxan-4-yl)-N,N,N-trimethylmethanaminium iodide nucleus has proved to be a suitable scaffold for its ability to give potent muscarinic agonists (1) or antagonists (2), depending on the size of the substituent in position 6 (methyl or bulkier groups, respectively) (2). Therefore, we designed, prepared and studied, at all five muscarinic receptor subtypes, analogs obtained by replacing the hydrophobic portion in position 6 of 2 with groups of different nature and bulk. The pharmacological profile of the novel compounds was evaluated by receptor binding assays on chinese hamster ovary (CHO) cells, expressing the five human muscarinic receptor subtypes (hM1-hM5). From preliminary results, compound 3 showed at all subtypes nM affinity values, which are comparable to those of some compounds used in therapy for the treatment of OAB. (1) Peretto, I.; Petrillo, P.; Imbimbo, B. P. Med. Res. Rev. 2009, 29, 867-902. (2) Piergentili, A.; Quaglia, W.; Giannella, M.; Del Bello, F.; Bruni, B.; Buccioni, M.; Carrieri, A.; Ciattini, S. Bioorg. Med. Chem. 2007, 15, 886-896.