Activation of cerebral function by CS-932, a functionally selective M1 partial agonist: neurochemical characterization and pharmacological studies.
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.
Iwata
N
N
Neuroscience and Immunology Research Laboratories, Sankyo Co., Ltd., Tokyo, Japan.
Kozuka
M
M
Hara
T
T
Kanek
T
T
Tonohiro
T
T
Sugimoto
M
M
Niitsu
Y
Y
Kondo
Y
Y
Yamamoto
T
T
Sakai
J
J
Nagano
M
M
D000818:Animals; D001667:Binding, Competitive; D001812:Blood-Brain Barrier; D016466:CHO Cells; D002540:Cerebral Cortex / Q000187:drug effects* / Q000502:physiology; D018678:Cholinergic Agents / Q000494:pharmacology; D006224:Cricetinae; D004336:Drug Antagonism; D004569:Electroencephalography; D006624:Hippocampus / Q000166:cytology / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D007555:Isoxazoles / Q000494:pharmacology*; D008252:Macaca fascicularis; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects; D051379:Mice; D018721:Muscarinic Agonists / Q000378:metabolism / Q000494:pharmacology*; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009474:Neurons / Q000502:physiology; D018697:Nootropic Agents / Q000378:metabolism / Q000494:pharmacology*; D011812:Quinuclidines / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D043643:Receptor, Muscarinic M1; D043585:Receptor, Muscarinic M2; D043587:Receptor, Muscarinic M3; D011976:Receptors, Muscarinic / Q000187:drug effects* / Q000378:metabolism; D012463:Saliva / Q000187:drug effects / Q000378:metabolism; D012601:Scopolamine / Q000494:pharmacology; D012894:Sleep Stages / Q000187:drug effects
C420685:CS 932; D018678:Cholinergic Agents; D007555:Isoxazoles; D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D018697:Nootropic Agents; D011812:Quinuclidines; D043643:Receptor, Muscarinic M1; D043585:Receptor, Muscarinic M2; D043587:Receptor, Muscarinic M3; D011976:Receptors, Muscarinic; D012601:Scopolamine