DESIGN, SYNTHESIS AND BIOLOGICAL EVALUATION OF NOVEL POTENT MUSCARINIC RECEPTOR ANTAGONISTS BEARING THE 1,4-DIOXANE NUCLEUS

The muscarinic acetylcholine receptor (mAChR) family consists of five closely related members (M1-M5) with different molecular and signaling properties. mAChRs mediate several functions in the central nervous system, as well as in the periphery. The 1,4-dioxane ring has recently demonstrated to be a bioversatile scaffold for the development of compounds binding mAChRs. In particular, we have demonstrated that it is possible to obtain mAChR agonists or antagonists, depending on the nature of the substituent in position 6 of the 1,4-dioxane nucleus. Specifically, the presence of bulky substituents in position 6 allowed us to obtain potent antagonists, including the 6,6-diphenyl derivative 1. In addition to quaternary ammonium compounds, such as 1, ligands bearing a tertiary amine (2) (Figure) also proved to act as antagonists at mAChRs, probably by binding in the cationic form. In this study, we have designed and synthesized the quaternary ammonium compounds 3-5 and the tertiary amines 6-8 by inserting in position 2 of the potent 6,6-diphenyl-1,4-dioxane mAChR antagonists 1 and 2, respectively, substituents of different steric bulk, with the aim of evaluating their role on the mAChR affinity. Moreover, considering the critical role of chirality in the mAChR affinity of 1,4-dioxanes, the enantiomers (+)-6 and (-)-6 were also prepared and studied. The most interesting result was obtained with the 2-methyl derivative 6 and its enantiomers which, surprisingly, in binding studies exhibited a biphasic curve, showing two distinct pKi values for all the five mAChRs. Molecular modelling studies were performed to rationalize this unexpected experimental observation.