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

抄録

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-DX116. 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.