title: Pharmacology of butylthio[2.2.2] (LY297802/NNC11-1053): a novel analgesic with mixed muscarinic receptor agonist and antagonist activity.
abstract: 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 neurotransmiter 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.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana, USA.
authors.forename: H E
authors.initials: HE
authors.lastname: Shannon
authors.forename: M J
authors.initials: MJ
authors.lastname: Sheardown
authors.forename: F P
authors.initials: FP
authors.lastname: Bymaster
authors.forename: D O
authors.initials: DO
authors.lastname: Calligaro
authors.forename: N W
authors.initials: NW
authors.lastname: Delapp
authors.forename: J
authors.initials: J
authors.lastname: Gidda
authors.forename: C H
authors.initials: CH
authors.lastname: Mitch
authors.forename: B D
authors.initials: BD
authors.lastname: Sawyer
authors.forename: P W
authors.initials: PW
authors.lastname: Stengel
authors.forename: J S
authors.initials: JS
authors.lastname: Ward
authors.forename: D T
authors.initials: DT
authors.lastname: Wong
authors.forename: P H
authors.initials: PH
authors.lastname: Olesen
authors.forename: P D
authors.initials: PD
authors.lastname: Suzdak
authors.forename: P
authors.initials: P
authors.lastname: Sauerberg
authors.forename: M D
authors.initials: MD
authors.lastname: Swedberg
mesh_terms: D000700:Analgesics / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D016275:Atrial Function; D001665:Binding Sites; D001833:Body Temperature Regulation / Q000187:drug effects; D002606:Charcoal; D018678:Cholinergic Agents / Q000378:metabolism / Q000494:pharmacology*; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D018377:Neurotransmitter Agents / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D012463:Saliva / Q000378:metabolism; D013830:Thiadiazoles / Q000378:metabolism / Q000494:pharmacology*; D014202:Tremor / Q000139:chemically induced; D001743:Urinary Bladder / Q000187:drug effects / Q000502:physiology; D014649:Vas Deferens / Q000187:drug effects / Q000502:physiology
chemical_list: D000700:Analgesics; D018678:Cholinergic Agents; D018377:Neurotransmitter Agents; D013830:Thiadiazoles; D002606:Charcoal; C101714:LY 297802