Delta opioid antagonist activity and binding studies of regioisomeric isothiocyanate derivatives of naltrindole: evidence for delta receptor subtypes

J Med Chem. 1992 Oct 30;35(22):4086-91. doi: 10.1021/jm00100a014.


The isothiocyanate group was attached to the 4'-, 5'-, 6'-, or 7'-position of naltrindole in an effort to determine the importance of the position of this electrophilic group on the selectivity for subtypes of delta opioid receptors. All of the ligands were delta-selective when tested against standard agonists in smooth muscle preparations. However, the rank-order delta antagonism of antinociception in mice did not parallel the in vitro pharmacologic data. The 5'-isothiocyanate 2 was the most potent and selective antagonist in vivo, causing a 52-fold increase of the ED50 for [D-Ser2,D-Leu5]enkephalin-Thr6 (DSLET) and no increase for [D-Pen2,D-Pen5]enkephalin (DPDPE). The effect of each of the ligands on the binding of [3H]DSLET and [3H]DPDPE to guinea pig brain membranes clearly differentiated between the binding sites that recognize these radioligands. These studies provide additional evidence for the presence of two subtypes of delta opioid receptors.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Binding, Competitive
  • Brain / metabolism
  • Guinea Pigs
  • In Vitro Techniques
  • Isomerism
  • Isothiocyanates*
  • Male
  • Mice
  • Morphinans
  • Muscle Contraction / drug effects
  • Muscle, Smooth / drug effects
  • Naltrexone / analogs & derivatives*
  • Naltrexone / chemical synthesis
  • Naltrexone / metabolism
  • Naltrexone / pharmacology
  • Narcotic Antagonists / chemical synthesis*
  • Narcotic Antagonists / metabolism
  • Narcotic Antagonists / pharmacology
  • Receptors, Opioid, delta / antagonists & inhibitors*
  • Receptors, Opioid, delta / classification*
  • Receptors, Opioid, delta / metabolism
  • Structure-Activity Relationship
  • Thiocyanates / chemical synthesis*
  • Thiocyanates / metabolism
  • Thiocyanates / pharmacology


  • Isothiocyanates
  • Morphinans
  • Narcotic Antagonists
  • Receptors, Opioid, delta
  • Thiocyanates
  • naltrindole 5'-isothiocyanate
  • Naltrexone