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.
Footnotes
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Send reprint requests to: J. M. Loudon, SmithKline Beecham Pharmaceuticals, New Frontiers Science Park, Third Avenue, Harlow CM19 5AW, UK.
- Abbreviations:
- AD
- Alzheimer’s disease
- SB 202026
- R-(Z)-(+)-α-(methoxyimino)-1-azabicyclo[2.2.2] octane-3-acetonitrile
- QNB
- quinuclidinyl benzilate
- OXO-M
- oxotremorine-M
- GABA
- γ-amino butyric acid
- fHHSiDF
- fluoro-hexahydro-siladifenidol
- CHO
- Chinese hamster ovary
- HM
- human muscarinic receptor subtype
- SCG
- superior cervical ganglion
- PBZ
- phenoxybenzamine
- RSA
- rhythmical slow wave activity
- BP
- blood pressure
- BPM
- beats per minute
- NO
- nitric oxide
- ChEIs
- cholinesterase inhibitors
- Received April 18, 1997.
- Accepted August 11, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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