3-(3-Alkylthio-1,2,5-thiadiazol-4-yl)-1-azabicycles. Structure-activity relationships for antinociception mediated by central muscarinic receptors

Article abstract of DOI:10.1016/0223-5234(96)89138-0

3-(3-Alkylthio-1,2,5-thiadiazol-4-yl)-1-azabicycles (quinuclidines 7a-f; exo-1-azanorbornanes 8a-f and endo-1-azanorbornanes 9a-f) constitute a new class of muscarinic antinociceptive agents. A novel route for the synthesis of these compounds was constructed starting from the azabicyclic ketones. The compounds showed high affinity for muscarinic receptors as evidenced by inhibition of [³H]oxotremorine-M ([³H]Oxo-M) binding to brain homogenate (IC₅₀ = 0.49-26 nM). In vivo, the compounds produced antinociception in the mouse grid shock test at doses well below those that produced salivation and tremor, with more than a 50-fold separation for some compounds. The enantiomers of 3-(3-butylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo[2.2.2]octane 7d exhibited little enantioselectivity with regard to either receptor affinity or analgesic activity.