Tacrine/Xanomeline hybrid ligands: synthesis and pharmacological evaluation at M1 muscarinic acetylcholine receptors and acetylcholinesterases

To further investigate the M1 muscarinic acetylcholine receptor subtype and to explore new, putative therapeutic approaches (1), we designed and synthesized novel hybrid orthosteric/allosteric ligands that incorporate in a common molecular skeleton two substructures, i.e., the pharmacophoric moieties of Xanomeline and Tacrine. Xanomeline is a M1/M4-preferring orthosteric agonist, endowed with promising antidementive properties in vivo (2). On the other hand, Tacrine is a well-known acetylcholinesterase (AChE) inhibitor that was also characterized as a M1/M2-preferring positive allosteric modulator (3). As illustrated below, we planned a set of novel bipharmacophoric ligands by linking the two molecular portions through polimethylene chains of different length. The target compounds were prepared both as tertiary amines and their corresponding quaternary methylammonium salts. The newly synthesized derivatives were assayed for their AChE inhibitory activity and appeared to be more potent AChE inhibitors than the parent compound Tacrine, displaying an activity trend related to the linker length. Moreover, the hybrids showed a lack of functional activity at M1 receptor subtype evaluated by using the IP-ONE test. The synthetic approach and the details of the pharmacological investigation will be illustrated and discussed. (1) Messerer, R.; Dallanoce, C.; De Amici, M.; Holzgrabe, U. Med. Chem. Commun., 2017, 8, 1346. (2) Fang, L.; Jumpertz, S.; Appenroth, D.; Fleck, C.; Mohr, K.; Tränkle, C.; Decker, M. J. Med. Chem. 2010, 53, 2094. (3) Kiefer-Day, J.S.; Campbell, H.E.; El-Fakahany, E.E. Eur. J. Pharmacol. 1991, 203, 421.