title: Pharmacological characterization of the bifunctional opioid ligand H-Dmt-Tic-Gly-NH-Bzl (UFP-505).
abstract: BACKGROUND
  While producing good-quality analgesia, µ-opioid (MOP) receptor activation produces a number of side-effects including tolerance. Simultaneous blockade of δ-opioid (DOP) receptors has been shown to reduce tolerance to morphine. Here, we characterize a prototype bifunctional opioid H-Dmt-Tic-Gly-NH-Bzl (UFP-505).
  
  
  METHODS
  We measured receptor binding affinity in Chinese hamster ovary (CHO) cells expressing recombinant human MOP, DOP, k-opioid (KOP), nociceptin/orphanin (NOP) receptors. For activation, we measured the binding of GTPγ(35)S to membranes from CHO(hMOP), CHO(hDOP), rat cerebrocortex, and rat spinal cord. In addition, we assessed 'end organ' responses in the guinea pig ileum and mouse vas deferens.
  
  
  RESULTS
  UFP-505 bound to CHO(hMOP) and CHO(hDOP) with (binding affinity) pK(i) values of 7.79 and 9.82, respectively. There was a weak interaction at KOP and NOP (pK(i) 6.29 and 5.86). At CHO(hMOP), UFP-505 stimulated GTPγ(35)S binding with potency (pEC(50)) of 6.37 and in CHO(hDOP) reversed the effects of a DOP agonist with affinity (pK(b)) of 9.81 (in agreement with pK(i) at DOP). UFP-505 also stimulated GTPγ(35)S binding in rat cerebrocortex and spinal cord with pEC(50) values of 6.11-6.53. In the guinea pig ileum (MOP-rich preparation), UFP-505 inhibited contractility with pEC(50) of 7.50 and in the vas deferens (DOP-rich preparation) reversed the effects of a DOP agonist with an affinity (pA(2)) of 9.15.
  
  
  CONCLUSIONS
  We have shown in a range of preparations and assays that UFP-505 behaves as a potent MOP agonist and DOP antagonist; a MOP/DOP bifunctional opioid. Further studies in dual expression systems and whole animals with this prototype are warranted.
authors.affiliation: Department of Cardiovascular Sciences, University of Leicester, Leicester Royal Infirmary, Leicester LE1 5WW, UK. dgl3@le.ac.uk
authors.forename: N
authors.initials: N
authors.lastname: Dietis
authors.forename: J
authors.initials: J
authors.lastname: McDonald
authors.forename: S
authors.initials: S
authors.lastname: Molinari
authors.forename: G
authors.initials: G
authors.lastname: Calo
authors.forename: R
authors.initials: R
authors.lastname: Guerrini
authors.forename: D J
authors.initials: DJ
authors.lastname: Rowbotham
authors.forename: D G
authors.initials: DG
authors.lastname: Lambert
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D015195:Drug Design; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000378:metabolism; D008024:Ligands; D008297:Male; D051379:Mice; D009842:Oligopeptides / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D011957:Receptors, Opioid / Q000378:metabolism; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D014649:Vas Deferens / Q000187:drug effects / Q000378:metabolism; D000094942:Nociceptin Receptor
chemical_list: C570557:H-Dmt-Tic-Gly-NH-Bzl; D008024:Ligands; D009842:Oligopeptides; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D000094942:Nociceptin Receptor