Copresence of 1,4-dioxane and quinuclidine nuclei in the design of novel muscarinic antagonists

The five muscarinic receptors are involved in many physiological functions and, therefore, the potential therapeutical applications of muscarinic agonists and antagonists are numerous. However, the high homology of the orthosteric binding sites of the different subtypes (amino acid sequence identity > 60%) makes particularly difficult the achievement of selective ligands (1). Candidates which are more likely to discriminate among subtypes are obviously antagonists because of their ability to interact with sites in the extracellular loops or with accessory residues of the receptor. In the search for novel muscarinic antagonists we opted for molecules bearing the 1,4-dioxane nucleus, which has proved to be a suitable scaffold for targeting muscarinic receptors (2). Such a scaffold, substituted in position 6 with two phenyl rings, has been linked by an oxymethylene bridge to a quinuclidine nucleus, which is present in numerous muscarinic agents as well. The presence of this nucleus has the advantage of including in the final compound a second stereogenic center, thus achieving a more selective effect, after the separation of the four enantiomers. The synthesis of the novel compounds, the characterization of their structure, and the preliminary pharmacological results will be discussed. References: 1) Eglen, R. M. Muscarinic receptor subtype pharmacology and physiology. Prog. Med. Chem. 2005, 43, 105-136. 2) Piergentili A.; Quaglia, W.; Del Bello, F.; Giannella, M.; Pigini, M.; Barocelli, E.; Bretoni, 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, 17, 8174-8185 and references therein