Binding affinity and selectivity of opioids at mu, delta and kappa receptors in monkey brain membranes

P. J. Emmerson, M. R. Liu, J. H. Woods, F. Medzihradsky

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220 Scopus citations


The binding parameters of radiolabeled DAMGO (mu), DPDPE and pCI-DPDPE (delta) and 5α, 7α, 8β-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro(4,5)dec- 8-yl]benzeneacetamide (also known as U69593, kappa) and the affinity and selectivity profiles of various opioid agonists and antagonists at the three opioid receptor types were determined in membranes from brain cortex of rhesus monkey. Among the 10 opioids with established mu-selective actions, etonitazene inhibited the binding of [3H]DAMGO with a K(i) of 0.02 nM (0.01 nM without sodium) and exhibited mu/delta and mu/kappa selectivities of 8800 and 11,650, respectively. DAMGO had a K(i) of 1.23 nM and was about 500-fold more selective at mu receptors compared with delta and kappa sites. Other mu opioids with higher than 100-fold binding selectivity were fentanil and sufentanil. Highly selective delta opioids were DPDPE, deltorphin II and naltrindole. With the exception of N,N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH, all investigated putative delta opioids bound to delta sites with low K(i)s, i.e., 0.04 nM, 0.13 nM and 1.4 nM for naltrindole, (±)-4-[(α-R*)-α- {(2S*, 5R*)-4-allyl-2,5-dimethyl-1-piperazinyl}-3-hydroxybenzyl]-N,N- diethylbenzamide and DPDPE, respectively. In this series, the displacement of [3H]pCI-DPDPE yielded results similar to those obtained with [3H]DPDPE. With nanomolar K(i)s of 0.70, 0.89, 0.25 and 0.06, respectively, the highest kappa selectivity was displayed by (trans)-(±)-3,4-dichloro-N-methyl-N-[2- (1-pyrrolidinyl)-cyclohexyl]benzeneacetamide and U69593, followed by dynorphin 1-13 and norbinaltorphimine. Both ethylketocyclazocine and bremazocine bound with high affinity to all three receptor types, showing a 15- to 127-fold preference for the kappa receptor. The binding of mu-, delta- , and kappa-selective agonists and antagonists exhibited distinct sensitivities to sodium. The results of this study, which revealed picomolar binding affinity and receptor selectivity up to 11,600-fold in the primate brain, should aid in interpreting opioid actions in vivo and in selecting receptor-specific ligands to characterize opioid receptor mechanisms in vitro.

Original languageEnglish (US)
Pages (from-to)1630-1637
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number3
StatePublished - 1994
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology


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