Opioid Antagonists and the A118G Polymorphism in the μ-Opioid Receptor Gene: Effects of GSK1521498 and Naltrexone in Healthy Drinkers Stratified by OPRM1 Genotype.

The A118G single-nucleotide polymorphism (SNP rs1799971) in the μ-opioid receptor gene, OPRM1, has been much studied in relation to alcohol use disorders. The reported effects of allelic variation at this SNP on alcohol-related behaviors, and on opioid receptor antagonist treatments, have been inconsistent. We investigated the pharmacogenetic interaction between A118G variation and the effects of two μ-opioid receptor antagonists in a clinical lab setting.

The novel mu-opioid antagonist, GSK1521498, reduces ethanol consumption in C57BL/6J mice.

Rationale: Using the drinking-in-the-dark (DID) model, we compared the effects of a novel mu-opioid receptor antagonist, GSK1521498, with naltrexone, a licensed treatment of alcohol dependence, on ethanol consumption in mice.

Objective: We test the ability of GSK1521498 to reduce alcohol consumption and compare its intrinsic efficacy to that of naltrexone by comparing the two drugs at doses matched for equivalent receptor occupancy.

Methods: Thirty-six C57BL/6J mice were tested in a DID procedure.

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

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.

Effects of the BDNF Val66Met polymorphism and met allele load on declarative memory related neural networks.

It has been suggested that the BDNF Val66Met polymorphism modulates episodic memory performance via effects on hippocampal neural circuitry. However, fMRI studies have yielded inconsistent results in this respect. Moreover, very few studies have examined the effect of met allele load on activation of memory circuitry.

The effects of alcohol on the pharmacokinetics and pharmacodynamics of the selective mu-opioid receptor antagonist GSK1521498 in healthy subjects.

The mu-opioid system has a key role in hedonic and motivational processes critical to substance addiction. However, existing mu-opioid antagonists have had limited success as anti-addiction treatments. GSK1521498 is a selective and potent mu-opioid antagonist being developed for the treatment of overeating and substance addictions.

Neural and behavioral effects of a novel mu opioid receptor antagonist in binge-eating obese people.

Background: Binge eating is associated with obesity and has been conceptualized as "food addiction." However, this view has received only inconsistent support in humans, and limited evidence relates key neurocircuitry to the disorder. Moreover, relatively few studies have used pharmacologic functional magnetic resonance imaging to probe the underlying basis of altered eating behaviors.

Effects of mu opioid receptor antagonism on cognition in obese binge-eating individuals.

Rationale: Translational research implicates the mu opioid neurochemical system in hedonic processing, but its role in dissociable high-level cognitive functions is not well understood. Binge-eating represents a useful model of 'behavioural addiction' for exploring this issue.

Objective: The aim of this study was to objectively assess the cognitive effects of a mu opioid receptor antagonist in obese individuals with binge-eating symptoms.

Opioid receptor modulation of hedonic taste preference and food intake: a single-dose safety, pharmacokinetic, and pharmacodynamic investigation with GSK1521498, a novel μ-opioid receptor inverse agonist.

Endogenous opioids and µ-opioid receptors have been linked to hedonic and rewarding aspects of palatable food intake. The authors examined the safety, pharmacokinetic, and pharmacodynamic profile of GSK1521498, a µ-opioid receptor inverse agonist that is being investigated primarily for the treatment of overeating behavior in obesity. In healthy participants, GSK1521498 oral solution and capsule formulations were well tolerated up to a dose of 100 mg.

Prolonged pharmacodynamic effects of S-0139, an intravenously administered endothelin A (ET) antagonist, in the human forearm blood flow model.

Aims: To estimate the pharmacologically active dose range of a new investigational compound S-0139, a selective endothelin A (ET(A)) receptor antagonist, in man, and to examine the duration of its pharmacodynamic effect.

Methods: Venous occlusion plethysmography was performed to assess changes in forearm blood flow following intra-brachial administration of endothelin-1 (ET-1). ET(A) antagonists have been shown to block ET-1-induced vasoconstriction in this model.

Lamotrigine does not prolong QTc in a thorough QT/QTc study in healthy subjects.

Aim: To characterize the effects of lamotrigine on QT interval in healthy subjects.

Methods: Healthy subjects received a single oral dose of moxifloxacin (400 mg) or placebo in crossover design, followed by a dose-escalating regimen of lamotrigine (n = 76) over a 77-day period, or matched placebo (n = 76). Blood samples were taken for determination of moxifloxacin and lamotrigine concentrations and digital 12-lead ECGs were recorded.