Jpn. J. Pharmacol. 84 (3), 266-280 (2000)

Activation of Cerebral Function by CS-932, a Functionally Selective M1 Partial Agonist: Neurochemical Characterization and Pharmacological Studies

Nobuyoshi Iwata1, Masao Kozuka1, Takao Hara1, Tsugio Kaneko1,*, Toshiyuki Tonohiro1, Masahiko Sugimoto1,
Yoichi Niitsu1, Yusuke Kondo1, Tsuneyuki Yamamoto2, Jun-ichi Sakai1 and Mitsuo Nagano1

1Neuroscience and Immunology Research Laboratories, Sankyo Co., Ltd., 2-58, Hiromachi 1-chome, Shinagawa-ku, Tokyo 140-8710, Japan
2Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, 1-1, Maidashi 3-chome, Higashi-ku, Fukuoka 812-8582, Japan
*Corresponding author.╩╩FAX:+81-3-5436-8566

Abstract: A newly synthesized agonist for muscarinic acetylcholine (ACh) receptors CS-932, (R)-3-(3-isoxazoloxy)-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 a- and b-waves, but decreased d-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.

Keywords: M1 agonist, Acetylcholine, Cerebral activation, Alzheimer disease

Copyrightę The Japanese Pharmacological Society 2000

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