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 Kaneko^1,*, Toshiyuki Tonohiro¹, Masahiko Sugimoto¹,
Yoichi Niitsu¹, Yusuke Kondo¹, Tsuneyuki Yamamoto², Jun-ichi Sakai¹ and Mitsuo Nagano<sup>1

1</sup>Neuroscience 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.ﾊﾊFAX:+81-3-5436-8566
E-mail: tkanek@shina.sankyo.co.jp

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ﾊ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