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OtherNEUROPHARMACOLOGY

Two New Potent Neurotransmitter Release Enhancers, 10,10-Bis(4-Pyridinylmethyl)-9(10H)-Anthracenone and 10,10-Bis(2-Fluoro-4-Pyridinylmethyl)-9(10H)-Anthracenone: Comparison to Linopirdine

R. Zaczek, R. J. Chorvat, J. A. Saye, M. E. Pierdomenico, C. M. Maciag, A. R. Logue, B. N. Fisher, D. H. Rominger and R. A. Earl
Journal of Pharmacology and Experimental Therapeutics May 1998, 285 (2) 724-730;
R. Zaczek
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R. J. Chorvat
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J. A. Saye
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M. E. Pierdomenico
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C. M. Maciag
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A. R. Logue
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B. N. Fisher
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D. H. Rominger
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Abstract

Linopirdine (3,3-bis(4-pyridinylmethyl)-1-phenylindolin-2-one, DUP996) is an extensively studied representative of a class of cognition enhancing compounds that increase the evoked release of neurotransmitters. Recent studies suggest that these agents act through the blockade of specific K+ channels. We have recently identified more potent anthracenone analogs of linopirdine: 10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone (XE991) and 10,10-bis(2-fluoro-4-pyridinylmethyl)-9(10H)-anthracenone (DMP 543). Although linopirdine possesses an EC50 of 4.2 μM for enhancement of [3H]ACh release from rat brain slices, XE991 and DMP 543 have EC50s of 490 and 700 nM, respectively. In addition to greater in vitro potency relative to linopirdine, both compounds show greater in vivopotency and duration of action. Although 5 mg/kg (p.o.) linopirdine does not lead to statistically significant increases in hippocampal extracellular acetylcholine levels, 5 mg/kg (p.o.) XE991 leads to increases (maximal effect > 90% over baseline) which are sustained for 60 min. Moreover, DMP 543 at 1 mg/kg causes more than a 100% increase in acetylcholine levels with the effect lasting more than 3 hr. At doses relevant to their release-enhancing properties, the only overt symptom consistently observed was tremor, possible via a cholinergic mechanism. These results suggest that XE991 and DMP 543 may prove to be superior to linopirdine as Alzheimer’s disease therapeutics. In addition, these agents should be useful pharmacological tools for probing the importance of particular ion channels in the control of neurotransmitter release.

Footnotes

  • Send reprint requests to: Dr. Robert Zaczek, The DuPont Merck Research Laboratories, Experimental Station E400/4458, Wilmington, DE 19880-0400.

  • Abbreviations:
    XE991
    10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone
    DMP543
    10,10-bis(2-fluoro-4-pyridinylmethyl)-9(10H)-anthracenone
    ACh
    acetylcholine
    DA
    dopamine
    IM
    M potassium current
    AD
    Alzheimer’s disease
    • Received August 25, 1997.
    • Accepted January 9, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 285, Issue 2
1 May 1998
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Two New Potent Neurotransmitter Release Enhancers, 10,10-Bis(4-Pyridinylmethyl)-9(10H)-Anthracenone and 10,10-Bis(2-Fluoro-4-Pyridinylmethyl)-9(10H)-Anthracenone: Comparison to Linopirdine
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OtherNEUROPHARMACOLOGY

Two New Potent Neurotransmitter Release Enhancers, 10,10-Bis(4-Pyridinylmethyl)-9(10H)-Anthracenone and 10,10-Bis(2-Fluoro-4-Pyridinylmethyl)-9(10H)-Anthracenone: Comparison to Linopirdine

R. Zaczek, R. J. Chorvat, J. A. Saye, M. E. Pierdomenico, C. M. Maciag, A. R. Logue, B. N. Fisher, D. H. Rominger and R. A. Earl
Journal of Pharmacology and Experimental Therapeutics May 1, 1998, 285 (2) 724-730;

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OtherNEUROPHARMACOLOGY

Two New Potent Neurotransmitter Release Enhancers, 10,10-Bis(4-Pyridinylmethyl)-9(10H)-Anthracenone and 10,10-Bis(2-Fluoro-4-Pyridinylmethyl)-9(10H)-Anthracenone: Comparison to Linopirdine

R. Zaczek, R. J. Chorvat, J. A. Saye, M. E. Pierdomenico, C. M. Maciag, A. R. Logue, B. N. Fisher, D. H. Rominger and R. A. Earl
Journal of Pharmacology and Experimental Therapeutics May 1, 1998, 285 (2) 724-730;
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