Muscarinic cholinergic agonists and antagonists of the 3-(3-alkyl-1,2,4-oxadiazol-5-yl)-1,2,5,6-tetrahydropyridine type. Synthesis and structure-activity relationships

J Med Chem. 1991 Feb;34(2):687-92. doi: 10.1021/jm00106a033.


A series of 3-(3-alkyl-1,2,4-oxadiazol-5-yl)-1,2,5,6-tetrahydro-1-methylpyr idines (2a-q) were synthesized and tested for central muscarinic cholinergic receptor binding affinity by using [3H]oxotremorine-M and [3H]QNB as ligands and in a functional assay using guinea pig ileum. The analogues with unbranched C1-8-alkyl substituents (2a-g) were agonists, whereas the compounds with branched or cyclic substituents (2h-m) were antagonists. The alkyl ether analogues (2o-q) were also agonists but had lower receptor binding affinity than the corresponding alkyl analogues. The 3-(5-alkyl-1,2,4-oxadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridi ne analogues had only ver low affinity for the central muscarinic receptors and were weak antagonists in the ileum assay. A few 3-(3-butyl-1,2,4-oxadiazol-5-yl)-1,2,5,6-tetrahydro-1-methylpyr idines substituted with methyl or hydrogen in the 1-, 5-, or 6-position were synthesized and tested. N-Desmethyl analogue 7 was a potent muscarinic agonist, whereas N-desmethyl-5-methyl analogue 11 and N-methyl-6-methyl analogue 13 both were antagonists with lower muscarinic receptor affinity. The 3-(3-butyl-1,2,4-oxadiazol-5-yl)quinuclidine (17) and tropane (15) analogues were both very potent antagonists with high affinity for central muscarinic receptors. The ratio [IC50(QNB)/IC50(Oxo-M)] x 0.162 proved to be a good indicator of the efficacy of the compounds in the guinea pig ileum assay.

MeSH terms

  • Animals
  • Azo Compounds / chemical synthesis*
  • Azo Compounds / metabolism
  • Azo Compounds / pharmacology
  • Brain / drug effects
  • Brain / metabolism
  • Chemical Phenomena
  • Chemistry
  • Guinea Pigs
  • Male
  • Muscle, Smooth / drug effects
  • Parasympatholytics / chemical synthesis*
  • Parasympatholytics / metabolism
  • Parasympatholytics / pharmacology
  • Parasympathomimetics / chemical synthesis*
  • Parasympathomimetics / metabolism
  • Parasympathomimetics / pharmacology
  • Pyridines / chemical synthesis*
  • Pyridines / metabolism
  • Pyridines / pharmacology
  • Rats
  • Receptors, Muscarinic / drug effects
  • Structure-Activity Relationship


  • Azo Compounds
  • Parasympatholytics
  • Parasympathomimetics
  • Pyridines
  • Receptors, Muscarinic