Activation of cerebral function by CS-932, a functionally selective M-1 partial agonist: Neurochemical characterization and pharmacological studies

A newly synthesized agonist for muscarinic acetylcholine (ACh) receptors CS -932, (R)-3-(3-isoxazoloxy)-1 -azabicyclo-[2.2.2]octane hydrochloride, show ed a relatively higher affinity for M-1 than M-2 receptors expressed in Chi nese hamster ovary (CHO)-cells in comparison with ACh. CS-932 elevated the intracellu- lar Ca2+ level only in M-1-CHO cells, although ACh increased th e level in both M-1- and M-3-CHO cells. CS-932 and ACh reduced forskolin-st imulated accumulation of cAMP in M-2-CHO cells by 20% and 80%, respectively . This neurochemical profile of CS-932 indicates that the compound can acti vate MI-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 an d decreased slow wave sleep episodes of daytime EEG in free-moving rats. It counteracted scopolamine-induced slow waves in rat cortical EEG. CS-932 al so increased the power of alpha- and beta -waves, but decreased delta -wave of the cortical EEG in anesthetized monkeys. It ameliorated scopolamine-in duced impairment of working memory in rats. Orally administered CS-932 had the best penetration into the brain among the muscarinic agonists tested an d caused the least salivary secretion among the cholinomimetics examined. T hese results indicate that CS-932 has potential as a cognitive enhancer wit h fewer side effects in therapy for Alzheimer disease.