Muscarinic agonists as analgesics. Antinociceptive activity versus M1 activity: SAR of alkylthio-TZTP's and related 1,2,5-thiadiazole analogs

Life Sci. 1995;56(11-12):807-14. doi: 10.1016/0024-3205(95)00014-w.

Abstract

Alkylthio-TZTPs (3-(3-alkylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-met hylpyridines) and corresponding azabicyclic analogs were tested for m1 efficacy in cloned human m1 receptors and for antinociceptive activity in the mouse grid shock assay. The m1 (%PI) SAR were distinctly different from the analgesia and the salivation SAR, suggesting that analgesia is mediated by neither m1 nor M3 muscarinic receptors.

MeSH terms

  • Analgesics / chemistry
  • Analgesics / pharmacology*
  • Animals
  • Carbachol / pharmacology
  • Dose-Response Relationship, Drug
  • Humans
  • Inhibitory Concentration 50
  • Mice
  • Molecular Structure
  • Muscarinic Agonists / chemistry
  • Muscarinic Agonists / pharmacology*
  • Pain Threshold / drug effects
  • Pain Threshold / physiology
  • Parasympathomimetics / chemistry
  • Parasympathomimetics / pharmacology*
  • Phosphatidylinositols / metabolism
  • Pyridines / chemistry
  • Pyridines / pharmacology*
  • Receptor, Muscarinic M1
  • Receptors, Muscarinic / metabolism*
  • Salivation / drug effects
  • Structure-Activity Relationship
  • Thiadiazoles / chemistry
  • Thiadiazoles / pharmacology*
  • Vocalization, Animal / drug effects

Substances

  • Analgesics
  • Muscarinic Agonists
  • Parasympathomimetics
  • Phosphatidylinositols
  • Pyridines
  • Receptor, Muscarinic M1
  • Receptors, Muscarinic
  • Thiadiazoles
  • 3-(3-(hexylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine
  • Carbachol