Transformation of a kappa-opioid receptor antagonist to a kappa-agonist by transfer of a guanidinium group from the 5'- to 6'-position of naltrindole

J Med Chem. 2001 Jun 21;44(13):2073-9. doi: 10.1021/jm010095v.


The importance of the indole scaffold of GNTI 3 in directing its address (5'-guanidinium group) to associate with the Glu297 residue of the kappa-opioid receptor was investigated by the synthesis and biological evaluation of its 4'- (4a), 6'- (4b), and 7'- (4c) regioisomers. The finding that only the 5'-regioisomer (GNTI) possessed potent kappa-opioid antagonist activity and high affinity at kappa-receptors illustrates the importance of the 5'-position in orienting the guanidinium group to the proper recognition locus (Glu 297) for potent kappa-antagonist activity. The discovery that the 6'-regioisomer of GNTI was a potent kappa-agonist, together with the results of site-directed mutagenesis studies that are consistent with association between the 6'-guanidinium group and Glu297, suggest that the transition from an inactive to an active state of the kappa-receptor involves a conformational change of TM6. We propose that association of the 6'-guanidinium group of 4b with Glu297 promotes axial rotational motion of transmembrane helix VI which leads to receptor activation via a conformational change of inner loop 3.

Publication types

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

MeSH terms

  • Animals
  • Cell Line
  • Cloning, Molecular
  • Guanidine / chemistry*
  • Guinea Pigs
  • Humans
  • In Vitro Techniques
  • Molecular Conformation
  • Muscle Contraction / drug effects
  • Muscle, Smooth / drug effects
  • Muscle, Smooth / metabolism
  • Mutagenesis, Site-Directed
  • Naltrexone / analogs & derivatives*
  • Naltrexone / chemistry*
  • Naltrexone / metabolism
  • Naltrexone / pharmacology*
  • Narcotic Antagonists / chemistry*
  • Narcotic Antagonists / metabolism
  • Narcotic Antagonists / pharmacology*
  • Rats
  • Receptors, Opioid, kappa / agonists*
  • Receptors, Opioid, kappa / antagonists & inhibitors*
  • Receptors, Opioid, kappa / metabolism
  • Structure-Activity Relationship
  • Transfection


  • Narcotic Antagonists
  • Receptors, Opioid, kappa
  • Naltrexone
  • naltrindole
  • Guanidine