Synthesis and in vitro biological profile of all four isomers of the potent muscarinic agonist 3-(3-methyl-1,2,4-oxadiazol-5-yl)-1-azabicyclo[2.2.1]heptane

J Med Chem. 1992 Mar 6;35(5):911-6. doi: 10.1021/jm00083a016.

Abstract

The four stereoisomers of the muscarinic agonist 7 have been synthesized from enantiomerically pure exo-azanorbornane esters (13a,b). The esters were obtained in optically active form by separation of the carboxamide diastereomers 12a,b, formed from the borane complex of exo-azanorbornane-3-carboxylate 10 and a chiral amine auxiliary. Using the known chirality of (R)-alpha-methylbenzylamine, an X-ray analysis was accomplished on 12a in order to determine the absolute configuration of the azanorbornane C4 chiral center. Each of the chiral esters 13a,b was separately transformed into the oxadiazoles with concomitant epimerization at C3 of the azanorbornane ring to afford the thermodynamic equilibrium mixture of isomers. Chromatographic separation followed by analysis of each isomer by NMR and GC allowed the absolute stereochemistry of all four isomers of 7 to be confirmed. Full biological evaluation in biochemical and pharmacological assays revealed that the 3R,4R isomer was the most active on receptor binding studies and the most potent on the pharmacological preparations, showing a 50-fold increase in potency at the M2 and M3 sites compared to M1.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Binding, Competitive
  • Bridged Bicyclo Compounds, Heterocyclic*
  • Electrophysiology
  • Ganglia, Sympathetic / drug effects
  • Ganglia, Sympathetic / physiology
  • Guinea Pigs
  • Heart Rate / drug effects
  • Ileum / drug effects
  • Ileum / physiology
  • Male
  • Molecular Conformation
  • Molecular Structure
  • Muscle Contraction / drug effects
  • Myenteric Plexus / drug effects
  • Myenteric Plexus / physiology
  • N-Methylscopolamine
  • Oxadiazoles / chemical synthesis*
  • Oxadiazoles / metabolism
  • Oxadiazoles / pharmacology
  • Parasympathomimetics / metabolism
  • Parasympathomimetics / pharmacology
  • Rats
  • Rats, Inbred Strains
  • Receptors, Muscarinic / drug effects
  • Receptors, Muscarinic / physiology*
  • Scopolamine Derivatives / metabolism
  • Stereoisomerism
  • Structure-Activity Relationship
  • X-Ray Diffraction

Substances

  • Bridged Bicyclo Compounds, Heterocyclic
  • Oxadiazoles
  • Parasympathomimetics
  • Receptors, Muscarinic
  • Scopolamine Derivatives
  • L 670548
  • N-Methylscopolamine