Hybrid molecules from xanomeline and 77-LH-28-1 as potential novel M1 muscarinic agonists

The five muscarinic acethylcoline receptors (M1-M5) mediate many physiological functions and, therefore, represent important therapeutic targets. The M1 muscarinic subtype, widely expressed post-synaptically in cortex and hippocampus, is involved in CNS disorders such as Alzheimer’s disease (AD). Therefore, ligands selectively activating this receptor subtype can be useful in the treatment of AD. Numerous attempts have been made to generate M1-selective agonists, but many of these efforts have failed, because most muscarinic agents (i.e. xanomeline) recognize the orthosteric acethylcoline binding site highly conserved in all the five subtypes. Recent extensive mutagenesis studies highlighted that the significant M1 preferential agonism displayed by 77-LH-28-1 [1] was consistent with an allosteric mode of interaction [2]. In this study, according to the hybrid molecule approach, novel muscarinic agonists have been designed, covalently connecting 77-LH-28-1 scaffold with xanomeline to obtain compounds potentially endowed with improved M1-selectivity and potency. The synthesis of the novel compounds and the preliminary pharmacological results, including the alcohol intermediates, will be discussed. References 1) Langmead, C. J.; Austin, N. E.; Branch, C. L.; Brown, J. T. et al Br. J. Pharmacol. 2008; 154, 1104-1115. 2) Lebon, G.; Langmead, C. J.; Tehan B. G.; Hulme, E. C. Mol. Pharmacol. 2009; 75, 331-341.