TY - JOUR T1 - SB 202026: A Novel Muscarinic Partial Agonist with Functional Selectivity for M<sub>1</sub> Receptors JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 1059 LP - 1068 VL - 283 IS - 3 AU - J. M. Loudon AU - S. M. Bromidge AU - F. Brown AU - M. S. G. Clark AU - J. P. Hatcher AU - J. Hawkins AU - G. J. Riley AU - G. Noy AU - B. S. Orlek Y1 - 1997/12/01 UR - http://jpet.aspetjournals.org/content/283/3/1059.abstract N2 - 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. The American Society for Pharmacology and Experimental Therapeutics ER -