Activation of Cerebral Function by CS-932, a Functionally Selective M_1 Partial Agonist : Neurochemical Characterization and Pharmacological Studies

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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<SUB>1</SUB> than M<SUB>2</SUB> receptors expressed in Chinese hamster ovary (CHO)-cells in comparison with ACh. CS-932 elevated the intracellular Ca<SUP>2+</SUP> level only in M<SUB>1</SUB>-CHO cells, although ACh increased the level in both M<SUB>1</SUB>- and M<SUB>3</SUB>-CHO cells. CS-932 and ACh reduced forskolin-stimulated accumulation of cAMP in M<SUB>2</SUB>-CHO cells by 20% and 80%, respectively. This neurochemical profile of CS-932 indicates that the compound can activate M<SUB>1</SUB>-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.

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  • The Japanese journal of pharmacology

    The Japanese journal of pharmacology 84(3), 266-280, 2000-11-01

    The Japanese Pharmacological Society

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各種コード

  • NII論文ID(NAID)
    10008186089
  • NII書誌ID(NCID)
    AA00691188
  • 本文言語コード
    ENG
  • 資料種別
    ART
  • ISSN
    00215198
  • NDL 記事登録ID
    5586812
  • NDL 雑誌分類
    ZS51(科学技術--薬学)
  • NDL 請求記号
    Z53-D199
  • データ提供元
    CJP書誌  NDL  J-STAGE 
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