PHARMACOLOGY OF BUTYLTHIO[2.2.2] (LY297802 NNC11-1053) - A NOVEL ANALGESIC WITH MIXED MUSCARINIC RECEPTOR AGONIST AND ANTAGONIST ACTIVITY/

Butylthio[2.2.2], -1,2,5-thiadiazol-3-yl)-1-azabicyclo[2.2.2]octane; L Y297802/NNC11-1053) is a muscarinic receptor ligand which is equieffic acious 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 neurotran smitter receptors and uptake sites. In isolated tissues, butylthio[2.2 .2] was an agonist with high affinity for M-1 receptors in the rabbit vas deferens (IC50 = 0.33 nM), but it was an antagonist at M-2 recepto rs in guinea pig atria (pA(2) = 6.9) and at M-3 receptors in guinea pi g urinary bladder (pA(2) = 7.4) and a weak partial agonist in guinea p ig ileum, which contains a heterogeneous population of muscarinic rece ptors. In viveo, 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 significa ntly alter heart rate in rats. Further, butylthio[2.2,2] did not produ ce parasympathomimetic effects such as salivation or tremor in mice, b ut it antagonized salivation and tremor produced by the nonselective m uscarinic agonist oxotremorine. The present data demonstrate that buty lthio[2.2.2] is a novel muscarinic receptor mixed agonist/antagonist a nd its pharmacological profile suggests that it may have clinical util ity in the management of pain as an alternative to opioids.