British Journal of Pharmacology (Br J Pharmacol)

Publisher: British Pharmacological Society, Wiley

Journal description

All aspects of experimental pharmacology including: Cellular and molecular pharmacology Biochemical pharmacology Neuroscience All aspects of general pharmacology Special Reports for rapid publication of important new results of special pharmacological significance The British Journal of Pharmacology is the leading 'original papers' publication in the field of general pharmacology.

Current impact factor: 4.84

Impact Factor Rankings

2016 Impact Factor Available summer 2017
2014 / 2015 Impact Factor 4.842
2013 Impact Factor 4.99
2012 Impact Factor 5.067
2011 Impact Factor 4.409
2010 Impact Factor 4.925
2009 Impact Factor 5.204
2008 Impact Factor 4.902
2007 Impact Factor 3.767
2006 Impact Factor 3.825
2005 Impact Factor 3.41
2004 Impact Factor 3.325
2003 Impact Factor 3.611
2002 Impact Factor 3.45
2001 Impact Factor 3.502
2000 Impact Factor 3.689
1999 Impact Factor 3.722
1998 Impact Factor 3.704
1997 Impact Factor 3.619
1996 Impact Factor 4.075
1995 Impact Factor 4.739
1994 Impact Factor 4.695
1993 Impact Factor 5.27
1992 Impact Factor 5.094

Impact factor over time

Impact factor
Year

Additional details

5-year impact 4.96
Cited half-life 7.50
Immediacy index 1.51
Eigenfactor 0.05
Article influence 1.32
Website British Journal of Pharmacology website
Other titles British journal of pharmacology (Online), BJP
ISSN 1476-5381
OCLC 39502220
Material type Document, Periodical, Internet resource
Document type Internet Resource, Computer File, Journal / Magazine / Newspaper

Publisher details

Wiley

  • Pre-print
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  • Post-print
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  • Restrictions
    • 12 months embargo
  • Conditions
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    • On author's personal website, institutional repositories, arXiv, AgEcon, PhilPapers, PubMed Central, RePEc or Social Science Research Network
    • Author's pre-print may not be updated with Publisher's Version/PDF
    • Author's pre-print must acknowledge acceptance for publication
    • Non-Commercial
    • Publisher's version/PDF cannot be used
    • Publisher source must be acknowledged with citation
    • Must link to publisher version with set statement (see policy)
    • If OnlineOpen is available, BBSRC, EPSRC, MRC, NERC and STFC authors, may self-archive after 12 months
    • If OnlineOpen is available, AHRC and ESRC authors, may self-archive after 24 months
    • Publisher last contacted on 07/08/2014
    • This policy is an exception to the default policies of 'Wiley'
  • Classification
    yellow

Publications in this journal

  • [Show abstract] [Hide abstract]
    ABSTRACT: Protease-activated receptors are a family of four GPCRs (PAR1 - 4) with a number of unique attributes. Nearly two-and-a-half decades after the discovery of the first PAR, an antagonist targeting this receptor has been approved for human use. The first-in-class PAR1 antagonist, vorapaxar, was approved in 2014 for use in the USA for the prevention of thrombotic cardiovascular events in patients with a history of myocardial infarction or with peripheral arterial disease. These recent developments indicate the clinical potential of manipulating PAR function. While much work has been aimed at uncovering the function of PAR1 and, to a lesser extent, PAR2, comparatively little is known regarding the pharmacology and physiology of PAR3 and PAR4. Recent studies have begun to develop the pharmacological and genetic tools required to study PAR4 function in detail, and there is now emerging evidence for the function of PAR4 in disease settings. In this review, we detail the discovery, structure, pharmacology, physiological significance, and therapeutic potential of PAR4. This article is protected by copyright. All rights reserved.
    No preview · Article · Feb 2016 · British Journal of Pharmacology
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    ABSTRACT: Background and purpose: Trimetazidine, known as a metabolic modulator, is an anti-anginal drug used for treatment of stable coronary artery disease (CAD). It is proposed to act via modulation of cardiac metabolism: shifting the mitochondrial substrate utilization towards carbohydrates, thus increasing the efficiency of adenosine triphosphate production. This mechanism was recently challenged, however using indirect approaches and animal models, making the conclusions of these studies questionable. The goal of the current study was to directly assess the effect of trimetazidine on mitochondrial substrate oxidation in left ventricular myocardium from CAD patients. Experimental approach: Mitochondrial fatty acid (palmitoylcarnitine) and carbohydrate (pyruvate) oxidation was measured in permeabilized left ventricular fibres obtained during coronary artery bypass grafting surgery from CAD patients, which either had trimetazidine included in their therapy (TMZ group) or not (Control). Key results: There was no difference between the two groups in either oxidation of palmitoylcarnitine or pyruvate, and no difference in the ratio of carbohydrate-to-fatty acid oxidation. Activity and expression of pyruvate dehydrogenase, the key regulator of carbohydrate metabolism, was also not different. Lastly, the acute in vitro exposure of myocardial tissue to different concentrations of trimetazidine did not affect myocardial oxidation of fatty acid. Conclusion and implications: Using myocardial tissue from a target CAD patient population, we found no effect of trimetazidine (applied chronically in vivo or acutely in vitro) on cardiac fatty acid and carbohydrate oxidation, suggesting that clinical effects of trimetazidine are unlikely due to its metabolic effects, but rather to yet unidentified intracardiac mechanism. This article is protected by copyright. All rights reserved.
    No preview · Article · Feb 2016 · British Journal of Pharmacology
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    ABSTRACT: Background and purpose: Activation of glucagon-like peptide-1 receptor (GLP-1R) exerts multiple cardioprotective effects. Geniposide (GE) is an agonist of GLP-1R, but its role in cardiac hypertrophy remains completely unknown. This study's aim was to investigate its protective effects and clarify the underlying molecular mechanisms. Experimental approach: Mice were subjected to constriction of the transverse aorta. And then GE was orally given for 7 week. Morphological changes, echocardiographic parameters, histological analyses, and hypertrophic markers were also used to evaluate hypertrophy. Key results: GE inhibited the hypertrophic response induced by constriction of the transverse aorta or by isoproterenol. Activation of AMPKα and mTOR, ERK and endoplasmic reticulum (ER) stress were observed in hypertrophic hearts that treated with GE. Furthermore, CpC or knock down of AMPKα restricted protections of GE against cell hypertrophy and activation of mTOR and ERK induced by hypertrophic stimuli. CpC or shAMPKα also abolished the protection of GE against ER stress induced by thapsigargin or dithiothreitol. The cardio-protective effects of GE were ablated in mice subjected to CpC. GLP-1 receptor blockade counteracted the anti-hypertrophic response and activation of AMPKα by GE. Knock down GLP-1R also offset the inhibitory effects of GE on cardiac hypertrophy in vivo. Conclusions and implications: GE protects against hypertrophy via activation of the GLP-1R/AMPKα pathway, and GE is a potential therapeutic drug for hypertrophy.
    No preview · Article · Feb 2016 · British Journal of Pharmacology
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    ABSTRACT: Antibody-based therapy of cancer employs monoclonal antibodies (mAbs) specific to soluble ligands, membrane antigens of T-lymphocytes or proteins located at the surface of cancer cells. The latter mAbs are often combined with cytotoxic regimens, because they block survival of residual fractions of tumours that evade therapy-induced cell death. Antibodies, along with kinase inhibitors, have become in the last decade the mainstay of oncological pharmacology. However, partial and transient responses, as well as emergence of tumour resistance, currently limit clinical application of mAbs. To overcome these hurdles, oligoclonal antibody mixtures are being tested in animal models and in clinical trials. The first homo-combination of two mAbs, each engaging a distinct site of HER2, an oncogenic receptor tyrosine kinase (RTK), has been approved for treatment of breast cancer. Likewise, a hetero-combination of antibodies to two distinct T-cell antigens, PD1 and CTLA4, has been approved for treatment of melanoma. In a similar vein, additive or synergistic anti-tumour effects observed in animal models has prompted clinical testing of hetero-combinations of antibodies simultaneously engaging distinct RTKs. We discuss the promise of antibody cocktails reminiscent of currently used mixtures of chemotherapeutics, and highlight mechanisms potentially underlying their enhanced clinical efficacy. This article is protected by copyright. All rights reserved.
    No preview · Article · Feb 2016 · British Journal of Pharmacology
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    ABSTRACT: Prostanoids from COX-2and PGE2 receptors (EP) contribute to vascular remodeling in different cardiovascular pathologies. This study evaluates the role of COX-2/EP1 axis on vascular remodeling and function in hypertension. Spontaneously hypertensive rats (SHR) and Angiotensin II (AngII, 1.44 mg∙Kg-1∙day-1, 2 weeks) infused mice were treated with the COX-2 inhibitor celecoxib (25 mg∙Kg-1∙day-1 i.p) or with the EP1 receptor antagonist SC19220 (10 mg∙Kg-1∙day-1 i.p.). COX-2-/- mice infused or not with AngII were also used. Celecoxib and SC19220 treatment did not modify the altered lumen diameter and wall:lumen observed in mesenteric resistance arteries from SHR and/or AngII-infused animals. However, both treatments and COX-2 deficiency decreased the augmented vascular stiffness observed in vessels from hypertensive animals. This was accompanied by diminished vascular collagen deposition, normalization of altered elastin structure and decreased connective tissue growth factor and plasminogen activator inhibitor-1 gene expression. COX-2 deficiency and SC19220 treatment diminished the increased vasoconstrictor responses and the endothelial dysfunction induced by AngII infusion. Hypertensive animals showed increased vascular mPGES-1 expression and increased vascular PGE2 production that was normalized by celecoxib. Celecoxib treatment also decreased the AngII-induced macrophage infiltration and TNF-α expression. Macrophage conditioned media (MCM) increased COX-2 and collagen type I expression in vascular smooth muscle cells. Celecoxib reduced the MCM-induced collagen type I expression. The COX-2/EP1 axis participates of the increased ECM deposition and vascular stiffness, the impaired vascular function and inflammation in hypertension. Targeting PGE2 receptors might have potential interest in hypertension-associated vascular damage. This article is protected by copyright. All rights reserved.
    No preview · Article · Feb 2016 · British Journal of Pharmacology
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    ABSTRACT: Asthma is characterized by chronic lung inflammation and airway hyper-responsiveness. Despite recent advances in understanding of its pathophysiology, asthma remains a major public health problem, and new therapeutic strategies are urgently needed. In this context, we sought to ascertain whether treatment with the tyrosine kinase inhibitor dasatinib might repair inflammatory and remodelling processes, thus improving lung function, in a murine model of asthma. Animals were sensitised and subsequently challenged with ovalbumin (OVA) or saline. Twenty-four hours after the last challenge, animals were treated with dasatinib, dexamethasone, or saline, every 12 hours for 7 consecutive days. Twenty-four hours after the last treatment, the animals were killed and data collected. Lung structure and remodelling were evaluated by morphometric analysis, immunohistochemistry, and transmission electron microscopy of lung sections. Inflammation was assessed by cytometric analysis and ELISA, and lung function was evaluated by invasive whole-body plethysmography. In OVA mice, dasatinib as well as dexamethasone led to significant reductions in airway hyper-responsiveness. Dasatinib was also able to attenuate alveolar collapse, contraction index, and collagen fibre deposition, as well as increase elastic fibre content, in OVA mice. Concerning the inflammatory process, dasatinib reduced inflammatory cell influx to the airway and lung-draining mediastinal lymph nodes, without inducing the thymic atrophy promoted by dexamethasone. In the model of allergic asthma used herein, dasatinib effectively blunted the inflammatory and remodelling processes in asthmatic lungs, enhancing airway repair and thus improving lung mechanics. This article is protected by copyright. All rights reserved.
    No preview · Article · Feb 2016 · British Journal of Pharmacology
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    ABSTRACT: Background and purpose: L-DOPA is still the most efficacious pharmacological treatment for Parkinson's disease. Its efficacy is counteracted after years of treatment by motor complications and notably L-DOPA-induced dyskinesia in the majority of patients. Evidence suggests that the serotonergic system is involved in the therapeutic and side effects of L-DOPA. Here, we investigate if long-term L-DOPA treatment alters the activity of dorsal raphe nucleus (DRN) and its reactivity to serotonergic drugs. Experimental approach: We explored the responses of serotonergic neurons to acute and chronic L-DOPA treatment using in vivo electrophysiological single unit-extracellular recordings in the 6-OHDA-lesion rat model of Parkinson's disease. Key results: The results showed that neither acute nor chronic L-DOPA administration (6 mg kg(-1) s.c.) altered the properties of serotonergic-like neurons. Furthermore, no correlation was found between the activity of these neurons and the magnitude of L-DOPA-induced dyskinesia. In dyskinetic rats, the inhibitory response induced by the 5-HT1A agonist 8-OH-DPAT (0.0625-16 µg kg(-1) , i.v.) was preserved. Nonetheless, L-DOPA impaired the ability of the serotonin reuptake inhibitor fluoxetine (0.125-8 mg kg(-1) , i.v) to inhibit DRN neuron firing rate in dyskinetic animals. Conclusions and implications: Although serotonergic neurons are responsible for the dopaminergic effects of L-DOPA, we provide evidence that the effect of L-DOPA is not related to changes of the activity of DRN neurons. Rather, L-DOPA might dampen the efficacy of drugs that normally enhance serotonin extracellular levels.
    No preview · Article · Jan 2016 · British Journal of Pharmacology
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    ABSTRACT: "Induced fit" binding of drugs to a target may lead to high affinity, selectivity and a long residence time and this mechanism has been proposed to apply to many drugs with high clinical efficacy It is a multi-step process that involves the initial binding to form a loose RL complex and a subsequent isomerisation/conformational change to yield a tighter binding R'L state. Equations with the same mathematical form may also describe the binding of bivalent antibodies and related synthetic drugs. Based on a selected range of "microscopic" rate constants and variables such as the ligand concentration and incubation time, we have presently simulated the experimental manifestations that may go along with induced fit binding. Overall, they validate different experimental procedures that have been used over the years to identify such binding mechanism. However, they also reveal that each of those manifestations only becomes perceptible at particular combinations of rate constants. The simulations also show that the durable nature of R'L and on the propensity of R'L to be formed repeatedly before the ligand dissociates will increase the residence time. This review may help pharmacologists and medicinal chemists to gather preliminary indications to identify an induced-fit mechanism.
    No preview · Article · Jan 2016 · British Journal of Pharmacology
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    ABSTRACT: Background and purpose: KCNQ-encoded voltage-dependent potassium channels (Kv7) are involved in the regulation of vascular tone. This study evaluated the influence of Kv7 channel-activation on smooth muscle relaxation in rat penile arteries and corpus cavernosum from normal and SHHF rats - a rat model of human metabolic syndrome. Experimental approach: qPCR and immunohistochemistry were used to determine the expression of KCNQ isoforms in penile tissue. Isometric tension was measured in intracavernous arterial rings and corpus cavernosum strips isolated from normal and SHHF rats. Key results: Transcripts for KCNQ3, KCNQ4, and KCNQ5 were detected in penile arteries and corpus cavernosum. KCNQ1 was only found in corpus cavernosum. Immunofluorescence signals to Kv7.4 and Kv7.5 were found in penile arteries, penile veins and corpus cavernosum. The Kv7.2-7.5 activators, ML213 and BMS204352, relaxed precontracted penile arteries and corpus cavernosum independently of NO synthase or endothelium-derived hyperpolarisation. Relaxations to sildenafil, a phosphodiesterase 5 inhibitor, and SNP, a NO donor, were reduced by blocking Kv7 channels with linopirdine in penile arteries and corpus cavernosum. In SHHF rat penile arteries and corpus cavernosum, relaxations to ML213 and BMS204352 were attenuated, and the blocking effect of linopirdine on sildenafil- and SNP-induced relaxations reduced. KCNQ3, KCNQ4, and KCNQ5 were downregulated and KCNQ1 was upregulated in corpus cavernosum from SHHF rats. KCNQ1-5 transcripts remained unchanged in penile arteries from SHHF rats. Conclusions and implications: These data suggest that Kv7 channels play a role in erectile function and contribute to the pathophysiology of erectile dysfunction, an early indicator of cardiovascular disease.
    No preview · Article · Jan 2016 · British Journal of Pharmacology
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    ABSTRACT: Background and purpose: Anatomical, biochemical and pharmacological evidences suggest the existence of a cross-talk between the orexinergic and the endocannabinoid system. While orexin receptor 1 (OX1) modulates the reinforcing properties of cannabinoids, the participation of orexins in the acute pharmacological effects of Δ9-tetrahydrocannabinol (THC) remains unexplored. Experimental approach: We assessed the possible role of orexins in THC-induced hypolocomotion, hypothermia, antinociception, anxiolytic- and anxiogenic-like effects, and memory impairment. Selective OX1 and OX2 antagonists, OX1 knockout (KO) mice as well as prepro-orexin (PPO) KO mice were used as pharmacological and genetic approaches. CB1 receptor levels in control and PPO KO mice were evaluated by immunoblot analysis. The expression of c-Fos after THC treatment was analyzed in several brain areas in wild-type and mice lacking the PPO gene. Key results: The hypothermia, supraspinal antinociception and anxiolytic-like effects induced by THC were modulated by orexins through OX2 signalling. OX1 did not seem to be involved in these THC responses. No differences in CB1 receptor levels were found between wild-type and PPO KO mice. THC-induced c-Fos expression was reduced in the central amygdala, medial preoptic area and lateral septum in these mutant mice. Conclusions and implications: Our results provide new findings to further clarify the interaction between orexins and cannabinoids. OX1 and OX2 are differently implicated in the pharmacological effects of cannabinoids.
    No preview · Article · Jan 2016 · British Journal of Pharmacology
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    ABSTRACT: Background and purpose: Biased GPCR ligands are able to engage with their target receptor in a manner that preferentially activates distinct downstream signalling and offers potential for next generation therapeutics. However, accurate quantification of ligand bias in vitro is complex and current best practice is not amenable for testing large compound numbers. We have therefore sought to apply ligand bias theory to an industrial scale screening campaign for the identification of new biased μ opioid receptor agonists. Experimental approach: μ opioid receptor assays with appropriate dynamic range were developed for both Gαi-dependent signalling and β-arrestin2 recruitment. Δlog(Emax/EC50) analysis was validated as an alternative for the operational model of agonism in calculating pathway bias towards Gαi-dependent signalling. The analysis was applied to a high throughput screen to characterise the prevalence and nature of pathway bias among a diverse set of compounds with μ opioid receptor agonist activity. Key results: An HTS screening campaign yielded 440 hits with greater than 10-fold bias relative to DAMGO. To validate these results, we quantified pathway bias of a subset of hits using the operational model of agonism. The high degree of correlation across these biased hits confirmed that Δlog(Emax/EC50) was a suitable method for identifying genuine biased ligands within a large diverse compound collection. Conclusions and implications: This work demonstrates that using Δlog(Emax/EC50); drug discovery can apply the concept of biased ligand quantification at scale and accelerate the deliberate discovery of novel therapeutics acting via this complex pharmacology. This article is protected by copyright. All rights reserved.
    No preview · Article · Jan 2016 · British Journal of Pharmacology
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    ABSTRACT: Background and purpose: Presynaptic, release-regulating metabotropic glutamate 2 and 3 (mGlu2/3) autoreceptors exist in central nervous system (CNS). They represent suitable targets for therapeutic approaches to central diseases that are typified by hyperglutamatergicity. The availability of specific ligands able to differentiate between mGlu2 and mGlu3 subunits allows to further characterize these autoreceptors. This study aims at investigating the pharmacological profile of mGlu2/3 receptors in selected CNS regions and at evaluating their functions in mice suffering from experimental autoimmune encephalomyelitis (EAE). Experimental approach: The comparative analysis of presynaptic mGlu2/3 autoreceptors was performed by analyzing the effect of selective mGlu2/3 receptor agonist(s) and antagonist(s) on the release of [(3) H]-D-aspartate from cortical and spinal cord synaptosomes in superfusion. Experiments were also carried out to analyze mGlu2/3 autoreceptor-mediated releasing functions in EAE animals and whether in vivo LY379268 administration can restore impaired glutamate release in these mice. Key results: Western blot analysis and confocal microscopy confirmed the presence of presynaptic mGlu2/3 receptor proteins. Cortical synaptosomes possess LY541850-sensitive, NAAG-insensitive autoreceptors having low affinity for LY379268, while LY541850-insensitive, NAAG-sensitive autoreceptors with high affinity for LY379268 exist in spinal cord terminals. In EAE mice, mGlu2/3 autoreceptors lost completely their inhibitory activity in cortical, but not in spinal cord synaptosomes. In vivo LY379268 (1-0.01 mg kg(-1) ) administration restored glutamate exocytosis capability in spinal cord but not in cortical terminals. Conclusions: We propose the existence of mGlu2-preferring and mGlu3-preferring autoreceptors in mouse cortex and spinal cord, respectively. The mGlu3-preferring autoreceptors could represent a target for new pharmacological approach for demyelinating diseases.
    No preview · Article · Jan 2016 · British Journal of Pharmacology
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    ABSTRACT: Background and purpose: Atrial metabolic remodelling is critical for the process of atrial fibrillation (AF). The peroxisome proliferator-activated receptor α (PPAR-α)/Sirtuin1 (Sirt1)/ PPAR co-activator α (PGC-1α) pathway plays an important role in maintaining energy metabolism. However, the effect of the PPAR-α agonist Fenofibrate (FB) on AF is unclear. Therefore, this study aimed to determine the effect of FB on atrial metabolic remodelling in AF and to explore possible mechanisms. Experimental approach: The expression of metabolic proteins was examined in the left atria of AF patients. Thirty-two rabbits were divided into the sham, AF (pacing with 600 beats/min for 1 week), FB treatment (pre-treated with FB before pacing), and FB alone treatment for 2 weeks groups. HL-1 cells were subjected to rapid pacing in the presence or absence of FB, the PPAR-α antagonist GW6471 or the Sirt1 specific inhibitor EX527. Metabolic factors, circulating biochemical metabolites, atrial electrophysiology, adenine nucleotide, glycogens and lipid droplet deposition were assessed. Key results: The PPAR-α/Sirt1/PGC-1α pathway was significantly inhibited in AF patients and the rabbit/HL-1 cell models, resulting in the reduction of key downstream metabolic factors; this effect was significantly restored by FB. FB markedly recovered the alterations in circulating biochemical metabolites, reduced the level of adenine nucleotides and the deposition of glycogen and lipid droplets, reversed the shortened atrial effective refractory period (AERP) and increased AF inducibility. Conclusion and implications: FB inhibited atrial metabolic remodelling in AF by regulating the PPAR-α/Sirt1/PGC-1α pathway. The present study may provide a novel therapeutic strategy for AF. This article is protected by copyright. All rights reserved.
    No preview · Article · Jan 2016 · British Journal of Pharmacology
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    ABSTRACT: Background and purpose: There is currently no medication approved specifically to treat cocaine addiction. Behavioural interventions such as cue exposure therapy (CET) rely heavily on new learning. Antagonism of the metabotropic glutamate 5 (mGlu5) receptor has emerged as a potential treatment, by reducing the reinforcing properties of cocaine. However, mGlu5 activity is necessary for learning; therefore such agents could interfere with behavioural treatments. We used a novel rodent model of CET to test the effects of mGlu5 negative and positive allosteric modulators (NAM and PAM) on behavioural therapy. Experimental approach: Rats were trained to lever press for cocaine in the presence of a discrete cue (conditioned stimulus, CS), and then extinguished in the absence of the CS. Following lever extinction, half the rats received CS extinction in the same chambers but with the levers withdrawn; the remaining rats received no CS extinction. Prior to this session rats received a systemic administration of either vehicle or an mGlu5 NAM (MTEP, Experiment 1) or PAM (CDPPB, Experiment 2). Cue-induced reinstatement was tested in a drug-free session the following day. Key results: At reinstatement, rats that had received CS extinction showed reduced responding. This effect was attenuated by MTEP treatment prior to CS extinction. On the other hand, administration of CDPPB (PAM) led to decreased reinstatement the following day, regardless of extinction condition. Conclusion and implications: This suggests that mGlu5 receptor activity is both necessary and sufficient for efficient extinction of a cocaine-associated CS. mGlu5 PAMs could therefore enhance the efficacy of CET.
    No preview · Article · Jan 2016 · British Journal of Pharmacology
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    ABSTRACT: Background and purpose: Ghrelin increases growth hormone secretion, gastric acid secretion, gastric motility and hunger but decreases glucose-dependent insulin secretion and insulin sensitivity in humans. Antagonizing the ghrelin receptor has the potential to be a therapeutic approach in the treatment of obesity and type 2 diabetes. Therefore, the aim was to pharmacologically characterize the novel small molecule antagonist PF-05190457 and assess translational pharmacology ex vivo. Experimental approach: Radioligand binding in filter and scintillation proximity assay formats were used to evaluate affinity, and europium-labeled guanosine 5'-triphosphate to assess functional activity. Rat vagal afferent firing and calcium imaging in dispersed islets were used as native tissues underlying food intake and insulin secretion, respectively. Key results: PF-05190457 was a potent and selective inverse agonist on constitutively active ghrelin receptors and acts as a competitive antagonist of ghrelin action, with a human Kd of 3 nM requiring 4 hours to achieve equilibrium. Potency of PF-05190457 was similar across different species. PF-05190457 increased intracellular calcium within dispersed islets and increased vagal afferent firing in a concentration-dependent manner with similar potency but was 3-fold less potent as compared to the in vitro Ki in recombinant over-expressing cells. The effect of PF-05190457 on rodent islets was comparable to glibenclamide but glucose-dependent and additive with the insulin secretagogue glucagon-like peptide-1. Conclusions and implications: Together these data provide the pharmacological in vitro and ex vivo characterization of the first ghrelin receptor inverse agonist which has advanced into clinical trials to evaluate the therapeutic potential of blocking ghrelin receptors in obesity and type 2 diabetes.
    No preview · Article · Jan 2016 · British Journal of Pharmacology
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    ABSTRACT: Background and purpose: Exposure-response (ER) modelling (concentration-QTc analysis) is gaining as much acceptance as the traditional by-time analysis of the placebo-adjusted change from baseline in the QTc interval (∆∆QTcF). It has been postulated that intensive ECG analysis and ER modelling during early phase drug development could be a cost-effective approach of estimating QT liability of a new drug, in a small number of subjects. Experimental approach: We used a highly-automated ECG analysis approach on ECGs from 46 subjects from a crossover TQT study to detect ∆∆QTcF with moxifloxacin. Using ECGs from these 46 subjects, we also simulated (bootstrapped) 1000 datasets of a parallel study with 8 subjects receiving moxifloxacin and 8 others receiving placebo. Key results: The slope from the concentration-QTc analysis for moxifloxacin in 46 subjects was 4.12 milliseconds of ∆∆QTcF per µg/ml; at mean Cmax of 2.95 µg/ml, estimated ∆∆QTcF was 13.4 ms (90% CI 11.3, 15.4 ms). In the 1000 simulated datasets, in 996 datasets ER modelling showed that the upper bound of the 90% CI for ∆∆QTcF at geometric mean Cmax exceeded 10 ms. In 895 of these 996 datasets the slope of the ER relationship was statistically significantly positive. Thus, with a small sample size (8 subjects on active drug and 8 on placebo), moxifloxacin-induced QTc prolongation was demonstrated using ER analysis with statistical power of >80%. Conclusions and implications: Our study adds to the growing body of data supporting intensive ECG collection and analysis in early phase studies to estimate QT liability.
    No preview · Article · Jan 2016 · British Journal of Pharmacology
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    ABSTRACT: Background and purpose: Repeated administration of a mu opioid receptor agonist can enhance some forms of impulsivity (e.g., delay discounting); however, it is unclear whether repeated administration impacts motor impulsivity. Experimental approach: This study examined the effects of acute administration of morphine and amphetamine prior to and during daily morphine administration in rats responding under a 5-choice serial reaction time task. Rats (n = 5) were trained to detect a brief flash of light presented randomly in one of 5 response holes; responding in the target hole delivered food, whereas responding in the wrong hole or responding prior to illumination of the target stimulus (premature response) initiated a timeout. Premature responding served as an index of motor impulsivity. Key results: Administered acutely, morphine (0.1-10 mg/kg, i.p.) increased omissions and modestly, though not significantly, premature responding without impacting response accuracy; amphetamine (0.1-1.78 mg/kg, i.p.) increased premature responding without impacting omissions or response accuracy. After 3 weeks of administration of 10 mg/kg/day morphine, tolerance developed to its effects on omissions whereas premature responding increased approximately 4-fold as compared to baseline. Effects of amphetamine were not significantly impacted by daily morphine administration. Conclusions and implications: These data suggest that repeated administration of morphine increases the effect of morphine on motor impulsivity even as tolerance develops to other effects (e.g., omissions). To the extent that impulsivity is a risk factor for drug abuse, repeated administration of mu opioid receptor agonists, for recreational or therapeutic purposes, might increase impulsivity and thus the risk for drug abuse. This article is protected by copyright. All rights reserved.
    No preview · Article · Jan 2016 · British Journal of Pharmacology