Activation of Cerebral Function by CS-932, a Functionally Selective M_1 Partial Agonist

• Published in: Japanese Journal of Pharmacology Vol. 84; no. 3; pp. 266 - 280
• Main Authors: Nobuyoshi Iwata, Masao Kozuka, Takao Hara, Tsugio Kaneko, Toshiyuki Tonohiro, Masahiko Sugimoto, Yoichi Niitsu, Yusuke Kondo, Tsuneyuki Yamamoto, Jun-ichi Sakai, Mitsuo Nagano
• Format: Journal Article
• Language: Japanese
• Published: The Japanese Pharmacological Society 2000
• ISSN: 0021-5198

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 M_1 than M_2 receptors expressed in Chinese hamster ovary (CHO)-cells in comparison with ACh. CS-932 elevated the intracellular Ca^2+ level only in M_1 -CHO cells, although ACh increased the level in both M_1 - and M_3 -CHO cells. CS-932 and ACh reduced forskolin-stimulated accumulation of cAMP in M_2 -CHO cells by 20% and 80%, respectively. This neurochemical profile of CS-932 indicates that the compound can activate M_1 -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 α- and β-waves, but decreased δ-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.