Vol. 281, Issue 2, 884-894, 1997

Pharmacology of Butylthio[2.2.2] (LY297802/NNC11-1053): A Novel Analgesic with Mixed Muscarinic Receptor Agonist and Antagonist Activity

Harlan E. Shannon, Malcolm J. Sheardown, Frank P. Bymaster, David O. Calligaro, Neil W. Delapp, Jaswant Gidda, Charles H. Mitch, Barry D. Sawyer, Peter W. Stengel, John S. Ward, David T. Wong, Preben H. Olesen, Peter D. Suzdak, Per Sauerberg and Michael D. B. Swedberg

Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana (H.E.S., F.P.B., D.O.C., N.W.D., J.G., C.H.M., B.D.S., P.W.S., J.S.W., D.T.W.) and Novo Nordisk A/S, Health Care Discovery, Novo Nordisk Park, DK-2760 Måløv, Denmark (P.H.O., M.J.S., M.D.B.S., P.D.S., P.S.)

Butylthio[2.2.2], ((+)-(S)-3-(4-butylthio-1,2,5-thiadiazol-3-yl)-1-azabicyclo[2.2.2]octane; LY297802/NNC11-1053) is a muscarinic receptor ligand which is equiefficacious to morphine in producing antinociception. In vitro, butylthio[2.2.2] had high affinity for muscarinic receptors in brain homogenates, but had substantially less or no affinity for several other neurotransmitter receptors and uptake sites. In isolated tissues, butylthio[2.2.2] was an agonist with high affinity for M₁ receptors in the rabbit vas deferens (IC₅₀ = 0.33 nM), but it was an antagonist at M₂ receptors in guinea pig atria (pA₂ = 6.9) and at M₃ receptors in guinea pig urinary bladder (pA₂ = 7.4) and a weak partial agonist in guinea pig ileum, which contains a heterogeneous population of muscarinic receptors. In vivo, butylthio[2.2.2] was without effect on acetylcholine, dopamine and serotonin levels in rat brain. Moreover, butylthio[2.2.2] did not decrease charcoal meal transit in mice, nor did it significantly alter heart rate in rats. Further, butylthio[2.2.2] did not produce parasympathomimetic effects such as salivation or tremor in mice, but it antagonized salivation and tremor produced by the nonselective muscarinic agonist oxotremorine. The present data demonstrate that butylthio[2.2.2] is a novel muscarinic receptor mixed agonist/antagonist and its pharmacological profile suggests that it may have clinical utility in the management of pain as an alternative to opioids.