Syntheses of novel pyridazinomorphinans by inverse electron demand cycloaddition and their binding to mu and kappa receptors

Arch Pharm (Weinheim). 1997 Jun;330(6):163-8. doi: 10.1002/ardp.19973300602.

Abstract

A number of novel pyridazinomorphinans have been synthesized by the inverse electron demand Diels-Alder reaction of various 3,6-disubstituted 1,2,4,5-tetrazines with enamines derived from dihydrocodeinone and with codeinone. Reduction of some of the pyridazinomorphinans did not furnish the expected pyrroloepoxymorphinans; in all cases investigated reductive cleavage of the epoxybridge was observed to yield dihydropyridazino- or pyrrolomorphinans. The structures of all new compounds were assigned by the spectral data, that of the cycloadduct of codeinone was additionally verified by X-ray crystallography. Compounds 5a, 8, 11a and 16 have been evaluated for their affinity at mu and kappa opioid receptors in radioligand binding assays. Their ability to inhibit [3H]DAMGO binding at mu and [3H]U 69.593 binding at kappa receptors, respectively as compared to codeine has been found to be lower.

MeSH terms

  • Animals
  • Benzeneacetamides*
  • Binding, Competitive
  • Cattle
  • Cell Membrane / metabolism
  • Corpus Striatum / metabolism
  • Crystallography, X-Ray
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
  • Enkephalins / metabolism
  • Indicators and Reagents
  • Models, Molecular
  • Molecular Structure
  • Morphinans / chemical synthesis*
  • Morphinans / chemistry
  • Morphinans / pharmacology
  • Pyrazines / chemical synthesis*
  • Pyrazines / chemistry
  • Pyrazines / pharmacology
  • Pyrrolidines / metabolism
  • Radioligand Assay
  • Receptors, Opioid, kappa / agonists
  • Receptors, Opioid, kappa / metabolism*
  • Receptors, Opioid, mu / agonists
  • Receptors, Opioid, mu / metabolism*

Substances

  • Benzeneacetamides
  • Enkephalins
  • Indicators and Reagents
  • Morphinans
  • Pyrazines
  • Pyrrolidines
  • Receptors, Opioid, kappa
  • Receptors, Opioid, mu
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
  • U 69593