SE-202026 - A NOVEL MUSCARINIC PARTIAL AGONIST WITH FUNCTIONAL SELECTIVITY FOR M-1 RECEPTORS

The finding that ascending cholinergic systems are severely degenerate d in Alzheimer's disease has driven the search for a cholinomimetic th erapy. Adverse effects observed with cholinesterase inhibitors and hig h-efficacy muscarinic agonists led us to design compounds with an impr oved profile. SE 202026 R-(Z)-(+)-alpha-(methoxyimino)-1-azabicyclo[2. 2.2] octane-3-acetonitrile) displaced [H-3]-oxotremorine-M from muscar inic receptors in the rat brain with high affinity (IC50 = 14 nM), a p otency similar to that of oxotremorine-M itself (IC50 = 13 nM), but ex hibited low affinity for cholinergic nicotinic receptors and other neu roreceptors. In studies using cloned human muscarinic receptors, SE 20 2026 possessed approximately equal affinity in displacing [H-3]-quinuc lidinyl benzilate from all muscarinic receptor subtypes. In functional models in vitro, SE 202026 caused maximal depolarization of the rat s uperior cervical ganglion at low concentrations (300 nM) (M-1-mediated effect), while producing a lower maximal effect than the high-efficac y agonists oxotremorine-M and carbachol on M-2-mediated release of ACh and M-3-mediated smooth muscle contraction (guinea pig ileum), respec tively. The functional selectivity and partial agonist profile seen in vitro were reflected in vivo through potent cognition-related activit y (M-1-induced increase in hippocampal EEG power) combined with low ef ficacy, compared with arecoline or oxotremorine, on induction of brady cardia (M-2-mediated response), hypotension (via M-3-mediated vasorela xation) and tremor (thought to be mediated by M-3 receptors). The fore going profile of SE 202026 predicted that cognition-enhancing activity would be achieved at doses below those that initiate undesirable side effects, and this has subsequently been demonstrated in rodents, marm osets and humans.