Benzocondensed derivatives as rigid analogues of the mu-opioid agonist 3(8)-cinnamyl-8(3)-propionyl-3,8-diazabicyclo[3.2.1]octanes: synthesis, modeling, and affinity

Farmaco. 1998 Oct-Nov;53(10-11):667-74. doi: 10.1016/s0014-827x(98)00084-6.

Abstract

A new series of rigid analogues (1a-g, 2a-g) of the previously reported analgesic 3-cinnamyl-8-propionyl-3,8-diazabicyclo[3.2.1]octane (I) and its reverted isomer 3-propionyl-8-cinnamyl (II) were synthesized, in which the cinnamyl substituent is incorporated in benzocondensed bicyclic systems. Binding assays for the affinity towards mu receptors indicated that, while in the reverted series 2 the beta-naphthylmethyl (2d) and the benzocycloheptenylmethyl derivative (2g) favorably compared with II, all compounds 1 displayed a mu-affinity lower than that of the parent I. Modeling studies suggest that the flexibility of the cinnamyl side chain plays an important role for activity.

MeSH terms

  • Analgesics, Opioid / chemical synthesis*
  • Analgesics, Opioid / metabolism
  • Analgesics, Opioid / pharmacology
  • Animals
  • Brain / metabolism
  • Bridged Bicyclo Compounds, Heterocyclic / chemical synthesis*
  • Bridged Bicyclo Compounds, Heterocyclic / metabolism
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
  • Enkephalins / pharmacology
  • Male
  • Mice
  • Models, Chemical
  • Molecular Conformation
  • Octanes / chemical synthesis*
  • Octanes / metabolism
  • Octanes / pharmacology
  • Pain / drug therapy
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Opioid, mu / agonists*
  • Receptors, Opioid, mu / metabolism
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Analgesics, Opioid
  • Bridged Bicyclo Compounds, Heterocyclic
  • Enkephalins
  • Octanes
  • Receptors, Opioid, mu
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)-