SB 202026: A Novel Muscarinic Partial Agonist with Functional Selectivity for M1 Receptors

• Published in: The Journal of pharmacology and experimental therapeutics 1997-12, Vol.283 (3), p.1059-1068
• Main Authors: Loudon, J M, Bromidge, S M, Brown, F, Clark, M S, Hatcher, J P, Hawkins, J, Riley, G J, Noy, G, Orlek, B S
• Format: Article
• Language: English
• Subjects: Acetylcholine - secretion; Animals; CHO Cells; Cricetinae; Dose-Response Relationship, Drug; Guinea Pigs; Hemodynamics - drug effects; Humans; Ileum - drug effects; Ileum - physiology; Imines - metabolism; Imines - pharmacology; Male; Mice; Muscarinic Agonists - pharmacology; Quinuclidines - metabolism; Quinuclidines - pharmacology; Rats; Receptor, Muscarinic M1; Receptors, Muscarinic - drug effects
• ISSN: 0022-3565; 1521-0103

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 [ 3 H]-oxotremorine-M from muscarinic receptors in the rat brain with high affinity (IC 50 = 14 nM), a potency similar to that of oxotremorine-M itself (IC 50 = 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 [ 3 H]-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) (M 1 -mediated effect), while producing a lower maximal effect than the high-efficacy agonists oxotremorine-M and carbachol on M 2 -mediated release of ACh and M 3 -mediated smooth muscle contraction (guinea pig ileum), respectively. The functional selectivity and partial agonist profile seen in vitro were reflected in vivo through potent cognition-related activity (M 1 -induced increase in hippocampal EEG power) combined with low efficacy, compared with arecoline or oxotremorine, on induction of bradycardia (M 2 -mediated response), hypotension ( via M 3 -mediated vasorelaxation) and tremor (thought to be mediated by M 3 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.