Abstract |
A newly synthesized agonist for muscarinic acetylcholine ( ACh) receptors CS-932, (R)-3-(3-iso-xazoloxy)-1-azabicyclo-[2.2.2] octane hydrochloride, showed a relatively higher affinity for M1 than M2 receptors expressed in Chinese hamster ovary (CHO)-cells in comparison with ACh. CS-932 elevated the intracellular Ca2+ level only in M1-CHO cells, although ACh increased the level in both M1- and M3-CHO cells. CS-932 and ACh reduced forskolin-stimulated accumulation of cAMP in M2-CHO cells by 20% and 80%, respectively. This neurochemical profile of CS-932 indicates that the compound can activate M1-receptor-mediated functions selectively. CS-932 increased firing of cholinoceptive neurons in rat hippocampal slices, and this excitation was antagonized by pirenzepine, but not by AF-DX 116. CS-932 increased awake and decreased slow wave sleep episodes of daytime EEG in free-moving rats. It counteracted scopolamine-induced slow waves in rat cortical EEG. CS-932 also increased the power of alpha- and beta-waves, but decreased delta-wave of the cortical EEG in anesthetized monkeys. It ameliorated scopolamine-induced impairment of working memory in rats. Orally administered CS-932 had the best penetration into the brain among the muscarinic agonists tested and caused the least salivary secretion among the cholinomimetics examined. These results indicate that CS-932 has potential as a cognitive enhancer with fewer side effects in therapy for Alzheimer disease.
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Authors | N Iwata, M Kozuka, T Hara, T Kanek, T Tonohiro, M Sugimoto, Y Niitsu, Y Kondo, T Yamamoto, J Sakai, M Nagano |
Journal | Japanese journal of pharmacology
(Jpn J Pharmacol)
Vol. 84
Issue 3
Pg. 266-80
(Nov 2000)
ISSN: 0021-5198 [Print] Japan |
PMID | 11138727
(Publication Type: Journal Article)
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Chemical References |
- CS 932
- Cholinergic Agents
- Isoxazoles
- Muscarinic Agonists
- Muscarinic Antagonists
- Nootropic Agents
- Quinuclidines
- Receptor, Muscarinic M1
- Receptor, Muscarinic M2
- Receptor, Muscarinic M3
- Receptors, Muscarinic
- Scopolamine
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Topics |
- Animals
- Binding, Competitive
- Blood-Brain Barrier
- CHO Cells
- Cerebral Cortex
(drug effects, physiology)
- Cholinergic Agents
(pharmacology)
- Cricetinae
- Drug Antagonism
- Electroencephalography
- Hippocampus
(cytology, physiology)
- Humans
- In Vitro Techniques
- Isoxazoles
(pharmacology)
- Macaca fascicularis
- Male
- Memory, Short-Term
(drug effects)
- Mice
- Muscarinic Agonists
(metabolism, pharmacology)
- Muscarinic Antagonists
(pharmacology)
- Neurons
(physiology)
- Nootropic Agents
(metabolism, pharmacology)
- Quinuclidines
(pharmacology)
- Radioligand Assay
- Rats
- Rats, Sprague-Dawley
- Rats, Wistar
- Receptor, Muscarinic M1
- Receptor, Muscarinic M2
- Receptor, Muscarinic M3
- Receptors, Muscarinic
(drug effects, metabolism)
- Saliva
(drug effects, metabolism)
- Scopolamine
(pharmacology)
- Sleep Stages
(drug effects)
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