1-(1,2,5-Thiadiazol-4-yl)-4-azatricyclo[2.2.1.0(2,6)]heptanes as New Potent Muscarinic M1 Agonists: Structure-Activity Relationship for 3-aryl-2-propyn-1-yloxy and 3-aryl-2-propyn-1-ylthio Derivatives

J Med Chem. 1999 Jun 3;42(11):1999-2006. doi: 10.1021/jm9910019.

Abstract

Two new series of 1-(1,2,5-thiadiazol-4-yl)-4-azatricyclo[2.2.1.0(2, 6)]heptanes were synthesized and evaluated for their in vitro activity in cell lines transfected with either the human M1 or M2 receptor. 3-Phenyl-2-propyn-1-yloxy and -1-ylthio analogues substituted with halogen in the meta position showed high functional potency, efficacy, and selectivity toward the M1 receptor subtype. A quite unique functional M1 receptor selectivity was observed for compounds 8b, 8d, 8f, 9b, 9d, and 9f. Bioavailability studies in rats indicated an oral bioavailability of about 20-30%, with the N-oxide as the only detected metabolite.

MeSH terms

  • Animals
  • Aza Compounds / chemical synthesis
  • Aza Compounds / chemistry*
  • Aza Compounds / pharmacokinetics
  • Aza Compounds / pharmacology
  • Binding, Competitive
  • Biological Availability
  • CHO Cells
  • Cell Line
  • Cerebral Cortex / metabolism
  • Cricetinae
  • Cyclic AMP / biosynthesis
  • Heptanes / chemical synthesis
  • Heptanes / chemistry*
  • Heptanes / pharmacokinetics
  • Heptanes / pharmacology
  • Humans
  • Hydrolysis
  • In Vitro Techniques
  • Mice
  • Muscarinic Agonists / chemical synthesis
  • Muscarinic Agonists / chemistry*
  • Muscarinic Agonists / pharmacokinetics
  • Muscarinic Agonists / pharmacology
  • Phosphatidylinositols / metabolism
  • Radioligand Assay
  • Rats
  • Receptor, Muscarinic M1
  • Receptor, Muscarinic M2
  • Receptors, Muscarinic / drug effects*
  • Receptors, Muscarinic / metabolism
  • Structure-Activity Relationship
  • Thiadiazoles / chemical synthesis
  • Thiadiazoles / chemistry*
  • Thiadiazoles / pharmacokinetics
  • Thiadiazoles / pharmacology
  • Transfection

Substances

  • Aza Compounds
  • Heptanes
  • Muscarinic Agonists
  • Phosphatidylinositols
  • Receptor, Muscarinic M1
  • Receptor, Muscarinic M2
  • Receptors, Muscarinic
  • Thiadiazoles
  • Cyclic AMP