Activation of cerebral function by CS-932, a functionally selective M1 partial agonist: neurochemical characterization and pharmacological studies

Jpn J Pharmacol. 2000 Nov;84(3):266-80. doi: 10.1254/jjp.84.266.

Abstract

A newly synthesized agonist for muscarinic acetylcholine (ACh) receptors CS-932, (R)-3-(3-iso-xazoloxy)-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 alpha- and beta-waves, but decreased delta-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.

MeSH terms

  • Animals
  • Binding, Competitive
  • Blood-Brain Barrier
  • CHO Cells
  • Cerebral Cortex / drug effects*
  • Cerebral Cortex / physiology
  • Cholinergic Agents / pharmacology
  • Cricetinae
  • Drug Antagonism
  • Electroencephalography
  • Hippocampus / cytology
  • Hippocampus / physiology
  • Humans
  • In Vitro Techniques
  • Isoxazoles / pharmacology*
  • Macaca fascicularis
  • Male
  • Memory, Short-Term / drug effects
  • Mice
  • Muscarinic Agonists / metabolism
  • Muscarinic Agonists / pharmacology*
  • Muscarinic Antagonists / pharmacology
  • Neurons / physiology
  • Nootropic Agents / metabolism
  • Nootropic Agents / pharmacology*
  • Quinuclidines / pharmacology*
  • Radioligand Assay
  • Rats
  • Rats, Sprague-Dawley
  • Rats, Wistar
  • Receptor, Muscarinic M1
  • Receptor, Muscarinic M2
  • Receptor, Muscarinic M3
  • Receptors, Muscarinic / drug effects*
  • Receptors, Muscarinic / metabolism
  • Saliva / drug effects
  • Saliva / metabolism
  • Scopolamine / pharmacology
  • Sleep Stages / drug effects

Substances

  • CS 932
  • Cholinergic Agents
  • Isoxazoles
  • Muscarinic Agonists
  • Muscarinic Antagonists
  • Nootropic Agents
  • Quinuclidines
  • Receptor, Muscarinic M1
  • Receptor, Muscarinic M2
  • Receptor, Muscarinic M3
  • Receptors, Muscarinic
  • Scopolamine