Development and characterisation of novel fentanyl-delta opioid receptor antagonist based bivalent ligands

M. F. Bird, R. S. Vardanyan, V. J. Hruby, G. Caló, R. Guerrini, S. Salvadori, C. Trapella, J. McDonald, D. J. Rowbotham, D. G. Lambert

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Background Opioid tolerance is a limiting factor in chronic pain. Delta opioid peptide (DOP)(δ) receptor antagonism has been shown to reduce tolerance. Here, the common clinical mu opioid peptide (MOP)(μ) receptor agonist fentanyl has been linked to the DOP antagonist Dmt-Tic (2′,6′-dimethyl-L-tyrosyl-1,2,3,4-tetrahydrisoquinoline-3-carboxylic acid) to create new bivalent compounds. Methods Binding affinities of bivalents(#9, #10, #11, #12 and #13) were measured in Chinese hamster ovary (CHO) cells expressing recombinant human MOP, DOP, Kappa opioid peptide (KOP)(κ) and nociceptin/orphanin FQ opioid peptide (NOP) receptors. Functional studies, measuring GTPγ[35S] or β-arrestin recruitment, were performed in membranes or whole cells respectively expressing MOP and DOP. Results The new bivalents bound to MOP (pKi: #9:7.31; #10:7.58; #11:7.91; #12:7.94; #13:8.03) and DOP (#9:8.03; #10:8.16; #11:8.17; #12:9.67; #13:9.71). In GTPγ[35S] functional assays, compounds #9(pEC50:6.74; intrinsic activity:0.05) #10(7.13;0.34) and #11(7.52;0.27) showed weak partial agonist activity at MOP. Compounds #12 and #13, with longer linkers, showed no functional activity at MOP. In antagonist assays at MOP, compounds #9 (pKb:6.87), #10(7.55) #11(7.81) #12(6.91) and #13(7.05) all reversed the effects of fentanyl. At DOP, all compounds showed antagonist affinity (#9:6.85; #10:8.06; #11:8.11; #12:9.42; #13:9.00), reversing the effects of DPDPE ([D-Pen2,5]enkephalin). In β-arrestin assays, compared with fentanyl (with response at maximum concentration (RMC):13.62), all compounds showed reduced ability to activate β-arrestin (#9 RMC:1.58; #10:2.72; #11:2.40; #12:1.29; #13:1.58). Compared with fentanyl, the intrinsic activity was: #9:0.12; #10:0.20; #11:0.18; #12:0.09 and #13:0.12. Conclusions The addition of a linker between fentanyl and Dmt-Tic did not alter the ability to bind to MOP and DOP, however a substantial loss in MOP functional activity was apparent. This highlights the difficulty in multifunctional opioid development.

Original languageEnglish (US)
Pages (from-to)646-656
Number of pages11
JournalBritish Journal of Anaesthesia
Issue number4
StatePublished - Apr 1 2015



  • delta receptors
  • fentanyl
  • mu receptors
  • opioid; pharmacology - analgesics opioid

ASJC Scopus subject areas

  • Anesthesiology and Pain Medicine

Cite this

Bird, M. F., Vardanyan, R. S., Hruby, V. J., Caló, G., Guerrini, R., Salvadori, S., Trapella, C., McDonald, J., Rowbotham, D. J., & Lambert, D. G. (2015). Development and characterisation of novel fentanyl-delta opioid receptor antagonist based bivalent ligands. British Journal of Anaesthesia, 114(4), 646-656.