Structural determinants of opioid activity in derivatives of 14-aminomorphinones: effects of changes to the chain linking of the C14-amino group to the aryl ring

J Med Chem. 2006 Oct 5;49(20):6104-10. doi: 10.1021/jm060595u.

Abstract

The 14-aminodihydromorphinone and codeinone series of opioid ligands have produced a number of ligands of substantial interest. To investigate the importance of the 14-substituent, a series of analogues in which the side chain length is varied and the amide and alkene functions are reduced have been prepared. Binding affinity, particularly at the mu-opioid receptor (MOR), was largely determined by the aromatic group of the side chain. In the [35S]GTPgammaS functional assay, the ligands having a three-carbon side chain were more potent antagonists than their longer chain counterparts, while shorter, two-carbon chain analogues were of higher MOR efficacy, an effect that was confirmed in vivo. Wash-resistant binding was observed within this series and appeared to be unrelated to side-chain length.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amines / chemical synthesis*
  • Amines / chemistry
  • Amines / pharmacology
  • Analgesics / chemical synthesis
  • Analgesics / chemistry
  • Analgesics / pharmacology
  • Animals
  • Cell Line
  • Cricetinae
  • Guanosine 5'-O-(3-Thiotriphosphate) / metabolism
  • Ligands
  • Mice
  • Morphine Derivatives / chemical synthesis*
  • Morphine Derivatives / chemistry
  • Morphine Derivatives / pharmacology
  • Narcotic Antagonists*
  • Pain Measurement
  • Radioligand Assay
  • Receptors, Opioid / agonists*
  • Receptors, Opioid / metabolism
  • Receptors, Opioid, delta / agonists
  • Receptors, Opioid, delta / antagonists & inhibitors
  • Receptors, Opioid, delta / metabolism
  • Receptors, Opioid, kappa / agonists
  • Receptors, Opioid, kappa / antagonists & inhibitors
  • Receptors, Opioid, kappa / metabolism
  • Receptors, Opioid, mu / agonists
  • Receptors, Opioid, mu / antagonists & inhibitors
  • Receptors, Opioid, mu / metabolism
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Amines
  • Analgesics
  • Ligands
  • Morphine Derivatives
  • Narcotic Antagonists
  • Receptors, Opioid
  • Receptors, Opioid, delta
  • Receptors, Opioid, kappa
  • Receptors, Opioid, mu
  • Guanosine 5'-O-(3-Thiotriphosphate)