Abstract

The finding that ascending cholinergic systems are severely degenerated in Alzheimer’s disease has driven the search for a cholinomimetic therapy. Adverse effects observed with cholinesterase inhibitors and high-efficacy muscarinic agonists led us to design compounds with an improved profile. SB 202026 (R-(Z)-(+)-α-(methoxyimino)-1-azabicyclo[2.2.2] octane-3-acetonitrile) displaced [³H]-oxotremorine-M from muscarinic receptors in the rat brain with high affinity (IC₅₀ = 14 nM), a potency similar to that of oxotremorine-M itself (IC₅₀ = 13 nM), but exhibited low affinity for cholinergic nicotinic receptors and other neuroreceptors. In studies using cloned human muscarinic receptors, SB 202026 possessed approximately equal affinity in displacing [³H]-quinuclidinyl benzilate from all muscarinic receptor subtypes. In functional models in vitro, SB 202026 caused maximal depolarization of the rat superior cervical ganglion at low concentrations (300 nM) (M₁-mediated effect), while producing a lower maximal effect than the high-efficacy agonists oxotremorine-M and carbachol on M₂-mediated release of ACh and M₃-mediated smooth muscle contraction (guinea pig ileum), respectively. The functional selectivity and partial agonist profile seen in vitro were reflected in vivothrough potent cognition-related activity (M₁-induced increase in hippocampal EEG power) combined with low efficacy, compared with arecoline or oxotremorine, on induction of bradycardia (M₂-mediated response), hypotension (viaM₃-mediated vasorelaxation) and tremor (thought to be mediated by M₃ receptors). The foregoing profile of SB 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, marmosets and humans.