title: The opioid receptor pharmacology of GSK1521498 compared to other ligands with differential effects on compulsive reward-related behaviours.
abstract: BACKGROUND
  The novel opioid receptor antagonist, GSK1421498, has been shown to attenuate reward-driven compulsive behaviours, such as stimulant drug seeking or binge eating, in animals and humans. Here, we report new data on the receptor pharmacology of GSK121498, in comparison to naltrexone, naloxone, 6-β-naltrexol and nalmefene.
  
  
  OBJECTIVE
  To determine whether the novel opioid antagonist, GSK1521498, is an orthosteric or allosteric antagonist at the μ opioid receptor (MOPr) and whether it has neutral antagonist or inverse agonist properties.
  
  
  METHODS
  A combination of radioligand binding assays and [(35)S]GTPγS binding assays was employed.
  
  
  RESULTS
  GSK1521498 completely displaced [(3)H]naloxone binding to MOPr and did not alter the rate of [(3)H]naloxone dissociation from MOPr observations compatible with it binding to the orthosteric site on MOPr. GSK1521498 exhibited inverse agonism when MOPr was overexpressed but not when the level of MOPr expression was low. In parallel studies under conditions of high receptor expression density, naloxone, naltrexone, 6-β-naltrexol and nalmefene exhibited partial agonism, not inverse agonism as has been reported previously for naloxone and naltrexone. In brain tissue from mice receiving a prolonged morphine pre-treatment, GSK1521498 exhibited slight inverse agonism.
  
  
  CONCLUSIONS
  Differences between GSK1521498 and naltrexone in their effects on compulsive reward seeking are arguably linked to the more selective and complete MOPr antagonism of GSK1521498 versus the partial MOPr agonism of naltrexone. GSK1521498 is also pharmacologically differentiated by its inverse agonist efficacy at high levels of MOPr expression, but this may be less likely to contribute to behavioural differentiation at patho-physiological levels of expression.
authors: School of Physiology and Pharmacology, University of Bristol, Bristol, BS8 1TD, UK.
authors: Eamonn
authors: E
authors: Kelly
authors: Stuart J
authors: SJ
authors: Mundell
authors: Anna
authors: A
authors: Sava
authors: Adelheid L
authors: AL
authors: Roth
authors: Antonio
authors: A
authors: Felici
authors: Kay
authors: K
authors: Maltby
authors: Pradeep J
authors: PJ
authors: Nathan
authors: Edward T
authors: ET
authors: Bullmore
authors: Graeme
authors: G
authors: Henderson
mesh_terms: D000701:Analgesics, Opioid / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D016466:CHO Cells; D003192:Compulsive Behavior / Q000188:drug therapy / Q000378:metabolism*; D006224:Cricetinae; D003412:Cricetulus; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007189:Indans / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D008024:Ligands; D008297:Male; D051379:Mice; D009020:Morphine / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D009270:Naloxone / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D009271:Naltrexone / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D009292:Narcotic Antagonists / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D011485:Protein Binding / Q000502:physiology; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012201:Reward; D016896:Treatment Outcome; D014230:Triazoles / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000701:Analgesics, Opioid; D007189:Indans; D008024:Ligands; C568078:N-((3,5-difluoro-3'-(1H-1,2,4-triazol-3-yl)-4-biphenylyl)methyl)-2,3-dihydro-1H-inden-2-amine; D009292:Narcotic Antagonists; D017450:Receptors, Opioid, mu; D014230:Triazoles; D009270:Naloxone; D016244:Guanosine 5'-O-(3-Thiotriphosphate); C010410:6 beta-hydroxynaltrexone; D009271:Naltrexone; D009020:Morphine; C038981:nalmefene