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The opioid receptor pharmacology of GSK1521498 compared to other ligands with differential effects on compulsive reward-related behaviours.

Kelly E, Mundell SJ, Sava A, Roth AL, Felici A, Maltby K, Nathan PJ, Bullmore ET, Henderson G - Psychopharmacology (Berl.) (2014)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: School of Physiology and Pharmacology, University of Bristol, Bristol, BS8 1TD, UK.

ABSTRACT

Rationale: 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.

Objectives: 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.

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Displacement of [3H]naloxone binding to MOPr. a–c Competition displacement binding curves for the displacement of 3H-naloxone binding by GSK1521498, naltrexone, and 6-β-naltrexol to membranes prepared from HEK293 cells expressing the human MOPr. d Kinetics of [3H]naloxone dissociation from MOPr in the absence and presence of GSK1521498, naltrexone and 6-β-naltrexol (all at 1 μM). Mean t1/2 values for [3H]naloxone dissociation in the presence of each drug are given with 95 % confidence limits
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Fig2: Displacement of [3H]naloxone binding to MOPr. a–c Competition displacement binding curves for the displacement of 3H-naloxone binding by GSK1521498, naltrexone, and 6-β-naltrexol to membranes prepared from HEK293 cells expressing the human MOPr. d Kinetics of [3H]naloxone dissociation from MOPr in the absence and presence of GSK1521498, naltrexone and 6-β-naltrexol (all at 1 μM). Mean t1/2 values for [3H]naloxone dissociation in the presence of each drug are given with 95 % confidence limits

Mentions: Competition displacement binding curves were constructed for the displacement of 3H-naloxone binding by GSK1521498, naltrexone and 6-β-naltrexol from MOPrs expressed in HEK293 cells. All three compounds displaced specific 3H-naloxone binding in a concentration-dependent manner with the maximum displacement being 100 % for each (Fig. 2a–c). pKi values calculated using the Cheng-Prussoff equation are given in Table 2. The order of affinity of binding to human MOPr was GSK1521498 > naltrexone = 6-β-naltrexol.Fig. 2


The opioid receptor pharmacology of GSK1521498 compared to other ligands with differential effects on compulsive reward-related behaviours.

Kelly E, Mundell SJ, Sava A, Roth AL, Felici A, Maltby K, Nathan PJ, Bullmore ET, Henderson G - Psychopharmacology (Berl.) (2014)

Displacement of [3H]naloxone binding to MOPr. a–c Competition displacement binding curves for the displacement of 3H-naloxone binding by GSK1521498, naltrexone, and 6-β-naltrexol to membranes prepared from HEK293 cells expressing the human MOPr. d Kinetics of [3H]naloxone dissociation from MOPr in the absence and presence of GSK1521498, naltrexone and 6-β-naltrexol (all at 1 μM). Mean t1/2 values for [3H]naloxone dissociation in the presence of each drug are given with 95 % confidence limits
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4281354&req=5

Fig2: Displacement of [3H]naloxone binding to MOPr. a–c Competition displacement binding curves for the displacement of 3H-naloxone binding by GSK1521498, naltrexone, and 6-β-naltrexol to membranes prepared from HEK293 cells expressing the human MOPr. d Kinetics of [3H]naloxone dissociation from MOPr in the absence and presence of GSK1521498, naltrexone and 6-β-naltrexol (all at 1 μM). Mean t1/2 values for [3H]naloxone dissociation in the presence of each drug are given with 95 % confidence limits
Mentions: Competition displacement binding curves were constructed for the displacement of 3H-naloxone binding by GSK1521498, naltrexone and 6-β-naltrexol from MOPrs expressed in HEK293 cells. All three compounds displaced specific 3H-naloxone binding in a concentration-dependent manner with the maximum displacement being 100 % for each (Fig. 2a–c). pKi values calculated using the Cheng-Prussoff equation are given in Table 2. The order of affinity of binding to human MOPr was GSK1521498 > naltrexone = 6-β-naltrexol.Fig. 2

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: School of Physiology and Pharmacology, University of Bristol, Bristol, BS8 1TD, UK.

ABSTRACT

Rationale: 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.

Objectives: 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.

Show MeSH
Related in: MedlinePlus