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Research ArticleArticle

Milameline (CI-979/RU35926): A Muscarinic Receptor Agonist with Cognition-Activating Properties: Biochemical and In Vivo Characterization

Roy D. Schwarz, Michael J. Callahan, Linda L. Coughenour, Melvin R. Dickerson, Jack J. Kinsora, William J. Lipinski, Charlotte A. Raby, Carolyn J. Spencer and Haile Tecle
Journal of Pharmacology and Experimental Therapeutics November 1999, 291 (2) 812-822;
Roy D. Schwarz
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Michael J. Callahan
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Linda L. Coughenour
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Melvin R. Dickerson
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Jack J. Kinsora
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William J. Lipinski
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Charlotte A. Raby
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Carolyn J. Spencer
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Haile Tecle
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Abstract

Milameline (E-1,2,5,6-tetrahydro-1-methyl-3-pyridinecarboxaldehyde,O-methyloxime monohydrochloride, CI-979, PD129409, RU35926) was characterized in vitro and evaluated for effects on central and peripheral cholinergic activity in rats and rhesus monkeys. In muscarinic binding studies, milameline displayed nanomolar affinity with an agonist ligand and micromolar affinity with antagonist ligands, with approximately equal affinities determined at the five subtypes of human muscarinic receptors (hM1–hM5) with whole cells or membranes from stably transfected Chinese hamster ovary (CHO) cells. On binding, milameline stimulated phosphatidylinositol hydrolysis in hM1 and hM3 CHO cells and inhibited forskolin-activated cAMP accumulation in hM2 and hM4 CHO cells. Additionally, it decreased K+-stimulated release of [3H]acetylcholine from rat cortical slices. Responses were not caused by the inhibition of acetylcholinesterase, and there was no significant binding to ∼30 other neurotransmitter binding sites. In rats, milameline decreased spontaneous and scopolamine-induced swimming activity, improved water-maze performance of animals impaired by basal forebrain lesions, increased cortical blood flow, decreased core body temperature, and increased gastrointestinal motility. Electroencephalogram activity in both rats and monkeys was characterized by a predominance of low-voltage desynchronized activity consistent with an increase in arousal. Milameline also reversed a scopolamine-induced impairment of attention on a continuous-performance task in monkeys. Thus, milameline possesses a pharmacological profile consistent with that of a partial muscarinic agonist, with central cholinergic actions being produced in rats and monkeys at doses slightly lower than those stimulating peripheral cholinergic receptors.

Footnotes

  • Send reprint requests to: Roy D. Schwarz, Ph.D., Neuroscience Therapeutics, Parke-Davis Pharmaceutical Research, 2800 Plymouth Rd., Ann Arbor, MI 48105. E-mail:roy.schwarz{at}wl.com

  • ↵1 This research was supported by the Warner-Lambert Company.

  • Abbreviations:
    AD
    Alzheimer’s disease
    AChEI
    acetylcholinesterase inhibitors
    ACh
    acetylcholine
    AChE
    acetylcholinesterase
    IBMX
    3-isobutyl-1-methylxanthine
    CNS
    central nervous system
    NMS
    N-methylscopolamine
    PI
    phosphatidylinositol
    GI
    gastrointestinal
    EEG
    electroencephalogram
    CMD
    cis-methyldioxolane
    QNB
    quinuclidinyl benzilate
    • Received May 12, 1999.
    • Accepted July 22, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 291 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 291, Issue 2
1 Nov 1999
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Research ArticleArticle

Milameline (CI-979/RU35926): A Muscarinic Receptor Agonist with Cognition-Activating Properties: Biochemical and In Vivo Characterization

Roy D. Schwarz, Michael J. Callahan, Linda L. Coughenour, Melvin R. Dickerson, Jack J. Kinsora, William J. Lipinski, Charlotte A. Raby, Carolyn J. Spencer and Haile Tecle
Journal of Pharmacology and Experimental Therapeutics November 1, 1999, 291 (2) 812-822;

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Research ArticleArticle

Milameline (CI-979/RU35926): A Muscarinic Receptor Agonist with Cognition-Activating Properties: Biochemical and In Vivo Characterization

Roy D. Schwarz, Michael J. Callahan, Linda L. Coughenour, Melvin R. Dickerson, Jack J. Kinsora, William J. Lipinski, Charlotte A. Raby, Carolyn J. Spencer and Haile Tecle
Journal of Pharmacology and Experimental Therapeutics November 1, 1999, 291 (2) 812-822;
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