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OtherANALGESIA AND DRUGS OF ABUSE

Butylthio[2.2.2] (NNC 11–1053/LY297802): An Orally Active Muscarinic Agonist Analgesic

Michael D. B. Swedberg, Malcolm J. Sheardown, Per Sauerberg, Preben H. Olesen, Peter D. Suzdak, Kristian T. Hansen, Frank P. Bymaster, John S. Ward, Charles H. Mitch, David O. Calligaro, Neil W. Delapp and Harlan E. Shannon
Journal of Pharmacology and Experimental Therapeutics May 1997, 281 (2) 876-883;
Michael D. B. Swedberg
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Malcolm J. Sheardown
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Per Sauerberg
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Preben H. Olesen
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Peter D. Suzdak
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Kristian T. Hansen
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Frank P. Bymaster
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John S. Ward
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Charles H. Mitch
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David O. Calligaro
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Neil W. Delapp
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Harlan E. Shannon
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Abstract

Butylthio[2.2.2] ((+)-(S)-3-(4-(Butylthio)-1,2,5-thiadiazol-3-yl)-1- azabicyclo[2.2.2] octane) is an agonist/antagonist at muscarinic receptors. The analgesic potential of butylthio[2.2.2] was assessed in the mouse by use of the grid-shock, tail-flick, hot-plate and writhing tests. The ED50 values ranged from 0.19 to 1.47 mg/kg and 1.51 to 12.23 mg/kg 30 min after s.c. and p.o. administration, respectively, yielding p.o./s.c. ratios ranging from 7 to 27. The ED50 values for salivation and tremor were >30 and 12.31 mg/kg s.c., and >60 and >60 mg/kg p.o., yielding therapeutic windows >130 and 54, and, >40 and >40, after s.c. and p.o. administration, respectively. Motor impairment or lethality were only seen at doses 116 and 254 times higher than the antinociceptive doses. Butylthio[2.2.2] was equieffective to, and 3- to 24-fold more potent than morphine. The duration of action was similar to that of morphine. The dose-response curve was shifted dose dependently to the right by the muscarinic antagonist scopolamine but not by the opioid antagonist naltrexone. The antinociceptive effect of butylthio[2.2.2] was reversed by the centrally acting muscarinic antagonist scopolamine but not by the peripherally acting muscarinic antagonist methscopolamine. After 6.5 days repeated dosing in mice, morphine produced marked tolerance, whereas butylthio[2.2.2] produced minimal, if any, tolerance. In the rat grid-shock test, ED50 values of 0.26 mg/kg s.c. and 25.28 mg/kg p.o. were obtained. These data show that butylthio[2.2.2] is a potent and efficacious antinociceptive with a very favorable therapeutic window after s.c. and p.o. administration in mice, and with good efficacy in rats.

Footnotes

  • Send reprint requests to: M. D. B. Swedberg, Ph.D., Novo Nordisk, Health Care Discovery, Novo Nordisk Park, DK-2760 Malov, Denmark.

  • ↵1 Portions of these data were presented to the Sixth International Symposium on Subtypes of Muscarinic Receptors at Ft. Lauderdale, FL, Nov. 9–12, 1994 (Swedberg et al., 1995b).

  • Abbreviations:
    CNS
    central nervous system
    ACh
    acetylcholine
    THA
    9-aminotetrahydroacridine
    RS86
    2-ethyl-8-methyl-2,8-diazaspiro-[4,5]-decan-1,3-dion hydrobromide
    alkylthio/oxy-TZTP
    3-(3-alkylthio/oxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methyl pyridine
    butylthio[2.2.2]
    (+)-(S)-3-(4-(Butylthio)-1,2,5-thiadiazol-3-yl)-1-azabicyclo[2.2.2]octane
    CL
    confidence limit
    • Received October 31, 1995.
    • Accepted January 31, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 281, Issue 2
1 May 1997
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OtherANALGESIA AND DRUGS OF ABUSE

Butylthio[2.2.2] (NNC 11–1053/LY297802): An Orally Active Muscarinic Agonist Analgesic

Michael D. B. Swedberg, Malcolm J. Sheardown, Per Sauerberg, Preben H. Olesen, Peter D. Suzdak, Kristian T. Hansen, Frank P. Bymaster, John S. Ward, Charles H. Mitch, David O. Calligaro, Neil W. Delapp and Harlan E. Shannon
Journal of Pharmacology and Experimental Therapeutics May 1, 1997, 281 (2) 876-883;

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OtherANALGESIA AND DRUGS OF ABUSE

Butylthio[2.2.2] (NNC 11–1053/LY297802): An Orally Active Muscarinic Agonist Analgesic

Michael D. B. Swedberg, Malcolm J. Sheardown, Per Sauerberg, Preben H. Olesen, Peter D. Suzdak, Kristian T. Hansen, Frank P. Bymaster, John S. Ward, Charles H. Mitch, David O. Calligaro, Neil W. Delapp and Harlan E. Shannon
Journal of Pharmacology and Experimental Therapeutics May 1, 1997, 281 (2) 876-883;
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