Design and synthesis of m1-selective muscarinic agonists: (R)-(-)-(Z)-1-Azabicyclo[2.2.1]heptan-3-one, O-(3-(3'-methoxyphenyl)-2-propynyl)oxime maleate (CI-1017), a functionally m1-selective muscarinic agonist

J Med Chem. 1998 Jul 2;41(14):2524-36. doi: 10.1021/jm960683m.

Abstract

The synthesis and SAR of a series of (Z)-(+/-)-1-azabicyclo[2.2. 1]heptan-3-one, O-(3-aryl-2-propynyl)oximes are described. The biochemistry and pharmacology of 24Z (PD 142505) and its enantiomers are highlighted. 24Z is functionally an m1-selective muscarinic agonist. Efficacy and m1 selectivity reside in the R enantiomer, (R)-24Z (CI-1017).

MeSH terms

  • 3T3 Cells
  • Adenylyl Cyclase Inhibitors
  • Animals
  • Bridged Bicyclo Compounds, Heterocyclic / chemical synthesis*
  • Bridged Bicyclo Compounds, Heterocyclic / metabolism
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology
  • Bridged Bicyclo Compounds, Heterocyclic / toxicity
  • CHO Cells
  • Cricetinae
  • Drug Design*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / toxicity
  • Humans
  • Inositol Phosphates / biosynthesis
  • Male
  • Memory / drug effects
  • Mice
  • Muscarinic Agonists / chemical synthesis*
  • Muscarinic Agonists / metabolism
  • Muscarinic Agonists / pharmacology
  • Muscarinic Agonists / toxicity
  • Oximes / chemical synthesis*
  • Oximes / metabolism
  • Oximes / pharmacology
  • Oximes / toxicity
  • Rats
  • Receptor, Muscarinic M1
  • Receptors, Muscarinic / drug effects*
  • Receptors, Muscarinic / metabolism
  • Stereoisomerism
  • Structure-Activity Relationship
  • Transfection

Substances

  • Adenylyl Cyclase Inhibitors
  • Bridged Bicyclo Compounds, Heterocyclic
  • Enzyme Inhibitors
  • Inositol Phosphates
  • Muscarinic Agonists
  • Oximes
  • Receptor, Muscarinic M1
  • Receptors, Muscarinic
  • PD 142505-0028