Identification of an opioid kappa receptor subtype-selective N-substituent for (+)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine

J Med Chem. 1998 Dec 17;41(26):5188-97. doi: 10.1021/jm980511k.


A three-component library of compounds was prepared in parallel using multiple simultaneous solution-phase synthetic methodology. The compounds were biased toward opioid receptor antagonist activity by incorporating (+)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine (a potent, nonselective opioid pure antagonist) as one of the monomers. The other two monomers, which included N-substituted or unsubstituted Boc-protected amino acids and a range of substituted aryl carboxylic acids, were selected to add chemical diversity. Screening of these compounds in competitive binding experiments with the kappa opioid receptor selective ligand [3H]U69,593 led to the discovery of a novel kappa opioid receptor selective ligand, N-¿(2'S)-[3-(4-hydroxyphenyl)propanamido]-3'-methylbutyl¿-(3R, 4R)-dimethyl-4-(3-hydroxyphenyl)piperidine (8, RTI-5989-29). Additional structure-activity relationship studies suggested that 8 possesses lipophilic and hydrogen-bonding sites that are important to its opioid receptor potency and selectivity. These sites appear to exist predominantly within the kappa receptor since the selectivity arises from a 530-fold loss of affinity of 8 for the mu receptor and an 18-fold increase in affinity for the kappa receptor relative to the mu-selective ligand, (+)-N-[trans-4-phenyl-2-butenyl]-(3R, 4R)-dimethyl-4-(3-hydroxyphenyl)piperidine (5a). The degree of selectivity observed in the radioligand binding experiments was not observed in the functional assay. According to its ability to inhibit agonist stimulated binding of [35S]GTPgammaS at all three opioid receptors, compound 8 behaves as a mu/kappa opioid receptor pure antagonist with negligible affinity for the delta receptor.

Publication types

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

MeSH terms

  • Animals
  • Binding, Competitive
  • Drug Evaluation, Preclinical
  • Guinea Pigs
  • In Vitro Techniques
  • Lactones / chemical synthesis*
  • Lactones / chemistry
  • Lactones / isolation & purification
  • Lactones / pharmacology
  • Ligands
  • Narcotic Antagonists / chemical synthesis*
  • Narcotic Antagonists / chemistry
  • Narcotic Antagonists / metabolism
  • Narcotic Antagonists / pharmacology
  • Piperidines / chemical synthesis*
  • Piperidines / chemistry
  • Piperidines / metabolism
  • Piperidines / pharmacology
  • Putamen / drug effects
  • Putamen / metabolism
  • Radioligand Assay
  • Receptors, Opioid, kappa / antagonists & inhibitors*
  • Receptors, Opioid, mu / antagonists & inhibitors
  • Structure-Activity Relationship


  • 6,7-diacetylalmuheptolide A
  • Lactones
  • Ligands
  • Narcotic Antagonists
  • Piperidines
  • RTI 5989-29
  • Receptors, Opioid, kappa
  • Receptors, Opioid, mu
  • almuheptolide A