Vol. 281, Issue 2, 876-883, 1997

Butylthio[2.2.2] (NNC 11-1053/LY297802): An Orally Active Muscarinic Agonist Analgesic¹

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

Novo Nordisk, Health Care Discovery, Malov, Denmark (M.D.B.S., M.J.S., P.S., P.O., P.D.S., K.T.H.) and Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (F.P.B., J.S.W., C.H.M., D.O.C., N.W.D., H.E.S.)

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.