Ligand/kappa-opioid receptor interactions: Insights from the X-ray crystal structure

Karina Martinez-Mayorga, Kendall G. Byler, Austin B. Yongye, Marc A. Giulianotti, Colette T. Dooley, Richard A. Houghten

Research output: Contribution to journalArticlepeer-review

12 Scopus citations


During the past five years, the three-dimensional structures of 14 different G-protein coupled receptors (GPCRs) have been resolved by X-ray crystallography. The most recently published structures, those of the opioid receptors (ORs), are remarkably important in pain modulation, drug addiction, and mood disorders. These structures, con firmed previously proposed key interactions conferring potency and antagonistic properties, including the well - known interaction with Asp138, conserved in all aminergic GPCRs. In addition, crystallization of the opioid receptors highlighted the potential function of the ECL2 and ICL2 loops. We have previously reported a set of potent and selective kappa opioid receptor peptide agonists, of which ff(D-nle)r-NH 2 is among the most potent and selective ones. These peptides were identified from the deconvolution of a 6,250,000 tetrapeptide combinatorial library. A derivative of this set is currently the subject of a phase 2 clinical trial in the United States. In this work, we describe comparative molecular modeling studies of kappa-OR peptide agonists with the co-crystallized antagonist, JDTic, and also report structure - activity relationships of 23 tetrapeptides. The overall binding and contact interactions are sound and interactions known to favor selectivity and potency were observed. Additional modeling studies will reveal conformational changes that the kappa-OR undergoes upon binding to these peptide agonists.

Original languageEnglish (US)
Pages (from-to)114-121
Number of pages8
JournalEuropean Journal of Medicinal Chemistry
StatePublished - 2013
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by the State of Florida, Executive Officer of the Governor's Department of Economic Development and funded, in part, by NIDA DA031370. KMM thanks DGAPA-UNAM (PAIIP IA200513-2). We would like to thank ChemAxon ( ) and StatSoft for kindly providing an academic license of their software.


  • Combinatorial chemistry
  • Kappa-opioid receptor
  • Molecular modeling
  • Tetrapeptide


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