N-3(9)-arylpropenyl-N-9(3)-propionyl-3,9-diazabicyclo[3.3.1]nonanes as mu-opioid receptor agonists. Effects on mu-affinity of arylalkenyl chain modifications

Bioorg Med Chem. 2002 Jun;10(6):1929-37. doi: 10.1016/s0968-0896(01)00436-9.

Abstract

Two series of N-3-arylpropenyl-N-9-propionyl-3,9-diazabicyclo[3.3.1]nonanes (1b-j) and of the reverted N-3-propionyl-N-9-arylpropenyl isomers (2b-j) as analogues of the previously reported analgesic N-3(9)-cinnamyl-N-9(3)-propionyl-3,9-diazabicyclo[3.3.1]nonanes (DBN) (1a, 2a) were synthesised and their affinity and selectivity towards opioid mu-, delta- and kappa-receptors were evaluated. Several compounds (1e,i,j-2d,e,f,g,j) exhibited a mu-affinity in the low nanomolar range with moderate or negligible affinity towards delta- and kappa-receptors. The representative term N-9-(3,3-diphenylprop-2-enyl)-N-3-propionyl-DBN (2d) displayed in vivo (mouse) a potent analgesic effect (ED(50) 3.88 mg/kg ip) which favourably compared with that of morphine (ED(50) 5 mg/kg ip). In addition, 2d produced in mice tolerance after a period twice as long with morphine.

MeSH terms

  • Analgesics, Opioid / chemical synthesis
  • Analgesics, Opioid / chemistry*
  • Analgesics, Opioid / metabolism
  • Analgesics, Opioid / pharmacology*
  • Animals
  • Brain / cytology
  • Bridged Bicyclo Compounds, Heterocyclic / chemical synthesis
  • Bridged Bicyclo Compounds, Heterocyclic / chemistry*
  • Bridged Bicyclo Compounds, Heterocyclic / metabolism
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology*
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Inhibitory Concentration 50
  • Male
  • Mice
  • Molecular Structure
  • Pain Measurement
  • Receptors, Opioid, mu / agonists*
  • Receptors, Opioid, mu / metabolism
  • Structure-Activity Relationship
  • Substrate Specificity

Substances

  • Analgesics, Opioid
  • Bridged Bicyclo Compounds, Heterocyclic
  • Receptors, Opioid, mu