Publications by authors named "Jim J Hagan"

37 Publications

Drug repositioning for Alzheimer's disease.

Nat Rev Drug Discov 2012 Nov;11(11):833-46

Wolfson Centre for Age-Related Diseases, King's College London, London SE1 1UL, UK.

Existing drugs for Alzheimer's disease provide symptomatic benefit for up to 12 months, but there are no approved disease-modifying therapies. Given the recent failures of various novel disease-modifying therapies in clinical trials, a complementary strategy based on repositioning drugs that are approved for other indications could be attractive. Indeed, a substantial body of preclinical work indicates that several classes of such drugs have potentially beneficial effects on Alzheimer's-like brain pathology, and for some drugs the evidence is also supported by epidemiological data or preliminary clinical trials. Here, we present a formal consensus evaluation of these opportunities, based on a systematic review of published literature. We highlight several compounds for which sufficient evidence is available to encourage further investigation to clarify an optimal dose and consider progression to clinical trials in patients with Alzheimer's disease.
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http://dx.doi.org/10.1038/nrd3869DOI Listing
November 2012

Enhanced appetitive learning and reversal learning in a mouse model for Prader-Willi syndrome.

Behav Neurosci 2012 Jun;126(3):488-92

Behavioural Genetics Group, School of Psychology, Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, UK.

Prader-Willi syndrome (PWS) is caused by lack of paternally derived gene expression from the imprinted gene cluster on human chromosome 15q11-q13. PWS is characterized by severe hypotonia, a failure to thrive in infancy and, on emerging from infancy, evidence of learning disabilities and overeating behavior due to an abnormal satiety response and increased motivation by food. We have previously shown that an imprinting center deletion mouse model (PWS-IC) is quicker to acquire a preference for, and consume more of a palatable food. Here we examined how the use of this palatable food as a reinforcer influences learning in PWS-IC mice performing a simple appetitive learning task. On a nonspatial maze-based task, PWS-IC mice acquired criteria much quicker, making fewer errors during initial acquisition and also reversal learning. A manipulation where the reinforcer was devalued impaired wild-type performance but had no effect on PWS-IC mice. This suggests that increased motivation for the reinforcer in PWS-IC mice may underlie their enhanced learning. This supports previous findings in PWS patients and is the first behavioral study of an animal model of PWS in which the motivation of behavior by food rewards has been examined.
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http://dx.doi.org/10.1037/a0028155DOI Listing
June 2012

Transcription and pathway analysis of the superior temporal cortex and anterior prefrontal cortex in schizophrenia.

J Neurosci Res 2011 Aug 27;89(8):1218-27. Epub 2011 Apr 27.

Computational Biology, Quantitative Sciences, Biopharmaceuticals, GlaxoSmithKline Medicines Research Centre, Stevenage, United Kingdom.

The molecular basis of schizophrenia is poorly understood; however, different brain regions are believed to play distinct roles in disease symptomology. We have studied gene expression in the superior temporal cortex (Brodmann area 22; BA22), which may play a role in positive pathophysiology, and compared our results with data from the anterior prefrontal cortex (BA10), which shows evidence for a role in negative symptoms. Genome-wide mRNA expression was determined in the BA22 region in 23 schizophrenics and 19 controls and compared with a BA10 data set from the same subjects. After adjustments for confounding sources of variation, we carried out GeneGO pathway enrichment analysis in each region. Significant differences were seen in age-related transcriptional changes between the BA22 and the BA10 regions, 21.8% and 41.4% of disease-associated transcripts showing age association, respectively. After removing age associated changes from our data, we saw the highest enrichment in processes mediating cell adhesion, synaptic contact, cytoskeletal remodelling, and apoptosis in the BA22 region. For the BA10 region, we observed the strongest changes in reproductive signalling, tissue remodelling, and cell differentiation. Further exploratory analysis also identified potentially disease-relevant processes that were undetected in our more stringent primary analysis, including autophagy in the BA22 region and the amyloid process in the BA10 region. Collectively, our analysis suggests disruption of many common pathways and processes underpinning synaptic plasticity in both regions in schizophrenia, whereas individual regions emphasize changes in certain pathways that may help to highlight pathway-specific therapeutic opportunities to treat negative or positive symptoms of the disease.
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http://dx.doi.org/10.1002/jnr.22647DOI Listing
August 2011

N-desmethylclozapine (NDMC) is an antagonist at the human native muscarinic M(1) receptor.

Neuropharmacology 2010 Jun 3;58(8):1206-14. Epub 2010 Mar 3.

Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park (North), Harlow, Essex CM19 5AW UK.

N-desmethylclozapine (NDMC) has been reported to display partial agonism at the human recombinant and rat native M(1) mAChR, a property suggested to contribute to the clinical efficacy of clozapine. However, the profile of action of NDMC at the human native M(1) mAChR has not been reported. The effect of NDMC on M(1) mAChR function was investigated in human native tissues by assessing its effect on (1) M(1) mAChR-mediated stimulation of [(35)S]-GTPgammaS-G(q/11)alpha binding to human post mortem cortical membranes and (2) the M(1) mAChR-mediated increase in neuronal firing in human neocortical slices. NDMC displayed intrinsic activities of 46+/-9%, compared to oxo-M, at the human recombinant M(1) receptor, in FLIPR studies and 35+/-4% at rat native M(1) receptors in [(35)S]-GTPgammaS-G(q/11)alpha binding studies. In [(35)S]-GTPgammaS-G(q/11)alpha binding studies in human cortex, oxo-M stimulated binding by 240+/-26% above basal with a pEC(50) of 6.56+/-0.05. In contrast, NDMC did not stimulate [(35)S]-GTPgammaS-G(q/11)alpha binding to human cortical membranes but antagonised the response to oxo-M (2microM) showing a pK(B) of 6.8, comparable to its human recombinant M(1) mAChR affinity (pK(i)=6.9) derived from [(3)H]-NMS binding studies. In human, contrary to the rat neocortical slices, NDMC did not elicit a significant increase in M(1) mAChR-mediated neuronal firing, and attenuated a carbachol-induced increase in neuronal firing when pre-applied. These data indicate that, whereas NDMC displays moderate to low levels of partial agonism at the human recombinant and rat native M(1) mAChR, respectively, it acts as an antagonist at the M(1) mAChR in human cortex.
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http://dx.doi.org/10.1016/j.neuropharm.2010.02.017DOI Listing
June 2010

Behavioural and cognitive abnormalities in an imprinting centre deletion mouse model for Prader-Willi syndrome.

Eur J Neurosci 2010 Jan 23;31(1):156-64. Epub 2009 Dec 23.

Laboratory of Cognitive and Behavioural Neuroscience, The Babraham Institute, Babraham Research Campus, Cambridge, UK.

The genes in the imprinted cluster on human chromosome 15q11-q13 are known to contribute to psychiatric conditions such as schizophrenia and autism. Major disruptions of this interval leading to a lack of paternal allele expression give rise to Prader-Willi syndrome (PWS), a neurodevelopmental disorder with core symptoms of a failure to thrive in infancy and, on emergence from infancy, learning disabilities and over-eating. Individuals with PWS also display a number of behavioural problems and an increased incidence of neuropsychiatric abnormalities, which recent work indicates involve aspects of frontal dysfunction. To begin to examine the contribution of genes in this interval to relevant psychological and behavioural phenotypes, we exploited the imprinting centre (IC) deletion mouse model for PWS (PWS-IC(+/-)) and the five-choice serial reaction time task (5-CSRTT), which is primarily an assay of visuospatial attention and response control that is highly sensitive to frontal manipulations. Locomotor activity, open-field behaviour and sensorimotor gating were also assessed. PWS-IC(+/-) mice displayed reduced locomotor activity, increased acoustic startle responses and decreased prepulse inhibition of startle responses. In the 5-CSRTT, the PWS-IC(+/-) mice showed deficits in discriminative response accuracy, increased correct reaction times and increased omissions. Task manipulations confirmed that these differences were likely to be due to impaired attention. Our data recapitulate several aspects of the PWS clinical condition, including findings consistent with frontal abnormalities, and may indicate novel contributions of the imprinted genes found in 15q11-q13 to behavioural and cognitive function generally.
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http://dx.doi.org/10.1111/j.1460-9568.2009.07048.xDOI Listing
January 2010

In vitro and in vivo comparison of two non-peptide tachykinin NK3 receptor antagonists: Improvements in efficacy achieved through enhanced brain penetration or altered pharmacological characteristics.

Eur J Pharmacol 2010 Feb 30;627(1-3):106-14. Epub 2009 Oct 30.

Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Harlow, Essex, UK.

Clinical evaluation of tachykinin NK(3) receptor antagonists has provided support for the therapeutic utility of this target in schizophrenia. However, these studies have not been entirely conclusive, possibly because of the pharmacokinetic limitations of these molecules. In the search for tachykinin NK(3) receptor antagonists with improved properties, we have discovered GSK172981 and GSK256471. Both compounds demonstrated high affinity for recombinant human (pK(i) values 7.7 and 8.9, respectively) and native guinea pig (pK(i) values 7.8 and 8.4, respectively) tachykinin NK(3) receptors. In vitro functional evaluations revealed GSK172981 to be a competitive antagonist (pA(2)=7.2) at cloned human tachykinin NK(3) receptor whereas GSK256471 diminished the neurokinin B-induced E(max) response, indicative of non-surmountable antagonist pharmacology (pA(2)=9.2). GSK172981 also exhibited a competitive profile in antagonizing neurokinin B-stimulated neuronal activity recorded from the guinea pig medial habenula slices (apparent pK(B)=8.1), whilst GSK256471 abolished the agonist-induced response. Central nervous system penetration by GSK172981 and GSK256471 was indicated by dose-dependent ex vivo tachykinin NK(3) receptor occupancy in medial prefrontal cortex (ED(50) values of 0.8 and 0.9 mg/kg, i.p., respectively) and the dose-dependent attenuation of agonist-induced "wet dog shake" behaviours in guinea pigs. Finally, in vivo microdialysis studies demonstrated that acute GSK172981 (30 mg/kg, i.p.) and GSK256471 (1mg/kg, i.p.) attenuated haloperidol-induced increases in extracellular dopamine in the guinea pig nucleus accumbens. Taken together, these in vitro and in vivo characterisations of the tachykinin NK(3) receptor antagonists GSK172981 and GSK256471 support their potential utility in the treatment of schizophrenia.
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http://dx.doi.org/10.1016/j.ejphar.2009.10.054DOI Listing
February 2010

Chronic fluoxetine differentially modulates the hippocampal microtubular and serotonergic system in grouped and isolation reared rats.

Eur Neuropsychopharmacol 2009 Nov 7;19(11):778-90. Epub 2009 Jul 7.

Institute of Neuroscience, School of Biomedical Sciences, University of Nottingham Medical School, Queen's Medical Centre, Nottingham, UK.

Social isolation from weaning in rats produces behavioural and hippocampal structural changes at adulthood. Here, rats were group or isolation reared for eight-weeks. Following the initial four-week period of rearing, fluoxetine (10 mg/kg i.p.) was administered for 28 days. Changes in recognition memory, hippocampal monoamines, and cytoskeletal microtubules were investigated. Isolation-rearing for four- or eight-weeks produced recognition memory deficits that were not reversed by fluoxetine. Eight-weeks of isolation decreased alpha-tubulin acetylation (Acet-Tub) and the tyrosinated/detyrosinated alpha-tubulin ratio (Tyr/Glu-Tub), suggesting major alterations in microtubule dynamics and neuronal plasticity. In grouped rats, fluoxetine decreased Acet-Tub without changes in Tyr/Glu-Tub. In isolates, fluoxetine did not affect Acet-Tub but increased Tyr/Glu-Tub. Finally, fluoxetine altered serotonin metabolism in grouped, but not in isolated animals. Therefore, isolation-rearing changes the hippocampal responses of the serotonergic and microtubular system to fluoxetine. These findings show that early-life experience induces behavioural changes paralleled by alterations in cytoskeletal and neurochemical functions.
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http://dx.doi.org/10.1016/j.euroneuro.2009.06.005DOI Listing
November 2009

Altered M(1) muscarinic acetylcholine receptor (CHRM1)-Galpha(q/11) coupling in a schizophrenia endophenotype.

Neuropsychopharmacology 2009 Aug 29;34(9):2156-66. Epub 2009 Apr 29.

Department of Cell Physiology & Pharmacology, Henry Wellcome Building, University of Leicester, Leicester, UK.

Alterations in muscarinic acetylcholine receptor (CHRM) populations have been implicated in the pathology of schizophrenia. Here we have assessed whether the receptor function of the M(1) subtype (CHRM1) is altered in a sub-population of patients with schizophrenia, defined by marked (60-80%) reductions in cortical [3H]-pirenzepine (PZP) binding, and termed 'muscarinic receptor-deficit schizophrenia' (MRDS). Using a [35S]-GTPgammaS-Galpha(q/11) immunocapture method we have assessed whether CHRM1 signalling in human cortex (Brodmann area 9 (BA9)) is altered in post mortem tissue from a MRDS group compared with a subgroup of patients with schizophrenia displaying normal PZP binding, and controls with no known history of psychiatric or neurological disorders. The CHRM agonist (oxotremorine-M) and a CHRM1-selective agonist (AC-42) increased Galpha(q/11)-[35S]-GTPgammaS binding, with AC-42 producing responses that were approximately 50% of those maximally evoked by the full agonist, oxotremorine-M, in control and subgroups of patients with schizophrenia. However, the potency of oxotremorine-M to stimulate Galpha(q/11)-[35S]-GTPgammaS binding was significantly decreased in the MRDS group (pEC(50) (M)=5.69+/-0.16) compared with the control group (6.17+/-0.10) and the non-MRDS group (6.05+/-0.07). The levels of Galpha(q/11) protein present in BA9 did not vary with diagnosis. Maximal oxotremorine-M-stimulated Galpha(q/11)-[35S]-GTPgammaS binding in BA9 membranes was significantly increased in the MRDS group compared with the control group. Similar, though non-statistically significant, trends were observed for AC-42. These data provide evidence that both orthosterically and allosterically acting CHRM agonists can stimulate a receptor-driven functional response ([35S]-GTPgammaS binding to Galpha(q/11)) in membranes prepared from post mortem human dorsolateral prefrontal cortex of patients with schizophrenia and controls . Furthermore, in a subgroup of patients with schizophrenia displaying markedly decreased PZP binding (MRDS) we have shown that although agonist potency may decrease, the efficacy of CHRM1-Galpha(q/11) coupling increases, suggesting an adaptative change in receptor-G protein coupling efficiency in this endophenotype of patients with schizophrenia.
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http://dx.doi.org/10.1038/npp.2009.41DOI Listing
August 2009

Fluoxetine administration modulates the cytoskeletal microtubular system in the rat hippocampus.

Synapse 2009 Apr;63(4):359-64

Institute of Neuroscience, School of Biomedical Sciences, University of Nottingham Medical School, Queen's Medical Centre, Nottingham, United Kingdom.

A number of studies suggest that stressful conditions can induce structural alterations in the hippocampus and that antidepressant drugs may prevent such deficits. In particular, the selective serotonin reuptake inhibitor (SSRI) fluoxetine was more effective in modulating different neuronal plasticity phenomena and related molecules in rat hippocampus. Cytoskeletal microtubule dynamics are fundamental to dendrites and axons remodeling, leading to the hypothesis that fluoxetine may affect the microtubular system. However, despite reports of stress-induced alterations in microtubule dynamics by different stressors, only few studies investigated the in vivo effects of antidepressants on microtubules in specific rat brain regions. The present study investigated the dose-related (1, 5, or 10 mg/kg i.p.) effects of acute and chronic (21 days) treatments with fluoxetine on the ratio of hippocampal alpha-tubulin isoforms which is thought to reflect microtubule dynamics. Western Blot analysis was used to quantify alpha-tubulin isoforms, high-performance liquid chromatography and fluorescence detection was used to measure ex vivo monoamine metabolism. The results showed that acute fluoxetine increased the stable forms acetylated and detyrosinated alpha-tubulin. Conversely, chronic fluoxetine decreased acetylated alpha-tubulin, indicative of increased microtubule dynamics. The neuron-specific Delta2-Tubulin was increased by chronic fluoxetine indicating neuronal involvement in the observed cytoskeletal changes. Although acute and chronic fluoxetine similarly altered serotonin metabolism by inhibition of serotonin reuptake, this showed no apparent correlation to the cytoskeletal perturbations. Our findings demonstrate that fluoxetine administration modulates microtubule dynamics in rat hippocampus. The cytoskeletal effect exerted by fluoxetine may eventually culminate in promoting events of structural neuronal remodeling.
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http://dx.doi.org/10.1002/syn.20614DOI Listing
April 2009

The selective 5-HT6 receptor antagonists SB-271046 and SB-399885 potentiate NCAM PSA immunolabeling of dentate granule cells, but not neurogenesis, in the hippocampal formation of mature Wistar rats.

Neuropharmacology 2008 Jun 1;54(8):1166-74. Epub 2008 Apr 1.

School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.

While there is now substantial evidence that 5-HT(6) antagonism leads to significantly improved cognitive ability, the mechanism(s) and/or pathway(s) involved are poorly understood. We have evaluated the consequence of chronic administration of the 5-HT(6) receptor antagonists SB-271046 and SB-399885 on neural cell adhesion molecule polysialylation state (NCAM PSA), a neuroplastic mechanism necessary for memory consolidation. Quantitative analysis of NCAM PSA immunopositive neurons in the dentate gyrus of drug-treated animals revealed a dose-dependent increase in polysialylated cell frequency following treatment with both SB-271046 and SB-399885. These effects could not be attributed to increased neurogenesis, as no difference in the rate of bromodeoxyuridine incorporation was apparent between the control and drug-treated groups. A substantial increase in the frequency of polysialylated cells in layer II of the entorhinal and perirhinal cortices was also observed, brain regions not previously associated with neurogenesis. Chronic treatment with SB-271046 or SB-399885 also significantly increased the activation of dentate polysialylation that is specific to learning. This effect does not occur with other cognition-enhancing drugs, such as tacrine, and this action potentially differentiates 5-HT(6) receptor antagonism as an unique neuroplastic mechanism for cognitive processes which may slow or reverse age/neurodegenerative related memory deficits.
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http://dx.doi.org/10.1016/j.neuropharm.2008.03.012DOI Listing
June 2008

Pharmacological assessment of m1 muscarinic acetylcholine receptor-gq/11 protein coupling in membranes prepared from postmortem human brain tissue.

J Pharmacol Exp Ther 2008 Jun 5;325(3):869-74. Epub 2008 Mar 5.

Department of Cell Physiology and Pharmacology, University of Leicester, Henry Wellcome Building, Lancaster Road, Leicester LE1 9HN, United Kingdom.

Using a selective Galpha(q/11) protein antibody capture guanosine 5'-O-(3-[35S]thio)triphosphate ([35S]GTPgammaS) binding approach, it has been possible to perform a quantitative pharmacological examination of the functional activity of the M(1) muscarinic acetylcholine receptor (mAChR) in membranes prepared from human postmortem cerebral cortex. Oxotremorine-M caused a > or = 2-fold increase in [35S]GTPgammaS-Galpha(q/11) binding with a pEC(50) of 6.06 +/- 0.16 in Brodmann's areas 23 and 25 that was almost completely inhibited by preincubation of membranes with the M(1) mAChR subtype-selective antagonist muscarinic toxin-7. In addition, the orthosteric and allosteric agonists, xanomeline [3(3-hexyloxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine] and AC-42 (4-n-butyl-1-[4-(2-methylphenyl)-4-oxo-1-butyl]-piperidine hydrogen chloride), increased [35S]-GTPgammaS-Galpha(q/11) binding, but with reduced intrinsic activities, inducing maximal responses that were 42 +/- 1 and 44 +/- 2% of the oxotremorine-M-induced response, respectively. These data indicate that the M(1) receptor is the predominant mAChR subtype coupling to the Galpha(q/11) G protein in these brain regions and that it is possible to quantify the potency and intrinsic activity of full and partial M(1) mAChR receptor agonists in postmortem human brain using a selective Galpha(q/11) protein antibody capture [35S]GTPgammaS binding assay.
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http://dx.doi.org/10.1124/jpet.108.137968DOI Listing
June 2008

1,2,4-triazol-3-yl-thiopropyl-tetrahydrobenzazepines: a series of potent and selective dopamine D(3) receptor antagonists.

J Med Chem 2007 Oct 15;50(21):5076-89. Epub 2007 Sep 15.

Psychiatry Centre of Excellence, Molecular Discovery Research, and Safety Assessment, GlaxoSmithKline Medicine Research Centre, Via Fleming 4, 37135 Verona, Italy.

The discovery of new highly potent and selective dopamine D3 receptor antagonists has recently permitted characterization of the role of the dopamine D3 receptor in a wide range of preclinical animal models. A novel series of 1,2,4-triazol-3-yl-thiopropyl-tetrahydrobenzazepines demonstrating a high level of D3 affinity and selectivity with an excellent pharmacokinetic profile is reported here. In particular, the pyrazolyl derivative 35 showed good oral bioavailability and brain penetration associated with high potency and selectivity in vitro. In vivo characterization of 35 confirmed that this compound blocks the expression of nicotine- and cocaine-conditioned place preference in the rat, prevents nicotine-triggered reinstatement of nicotine-seeking behavior in the rat, reduces oral operant alcohol self-administration in the mouse, increases extracellular levels of acetylcholine in the rat medial prefrontal cortex, and potentiates the amplitude of the relative cerebral blood volume response to d-amphetamine in a regionally specific manner in the rat brain.
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http://dx.doi.org/10.1021/jm0705612DOI Listing
October 2007

SB-649915-B, a novel 5-HT1A/B autoreceptor antagonist and serotonin reuptake inhibitor, is anxiolytic and displays fast onset activity in the rat high light social interaction test.

Neuropsychopharmacology 2007 Oct 14;32(10):2163-72. Epub 2007 Mar 14.

Schizophrenia and Bipolar Research, Psychiatry Centre of Excellence in Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Essex CM19 5AW, UK.

Preclinically, the combination of an SSRI and 5-HT autoreceptor antagonist has been shown to reduce the time to onset of anxiolytic activity compared to an SSRI alone. In accordance with this, clinical data suggest the coadministration of an SSRI and (+/-) pindolol can decrease the time to onset of anxiolytic/antidepressant activity. Thus, the dual-acting novel SSRI and 5-HT(1A/B) receptor antagonist, SB-649915-B, has been assessed in acute and chronic preclinical models of anxiolysis. SB-649915-B (0.1-1.0 mg/kg, i.p.) significantly reduced ultrasonic vocalization in male rat pups separated from their mothers (ED(50) of 0.17 mg/kg). In the marmoset human threat test SB-649915-B (3.0 and 10 mg/kg, s.c.) significantly reduced the number of postures with no effect on locomotion. In the rat high light social interaction (SI), SB-649915-B (1.0-7.5 mg/kg, t.i.d.) and paroxetine (3.0 mg/kg, once daily) were orally administered for 4, 7, and 21 days. Ex vivo inhibition of [(3)H]5-HT uptake was also measured following SI. SB-649915-B and paroxetine had no effect on SI after 4 days. In contrast to paroxetine, SB-649915-B (1.0 and 3.0 mg/kg, p.o., t.i.d.) significantly (p<0.05) increased SI time with no effect on locomotion, indicative of an anxiolytic-like profile on day 7. Anxiolysis was maintained after chronic (21 days) administration by which time paroxetine also increased SI significantly. 5-HT uptake was inhibited by SB-649915-B at all time points to a similar magnitude as that seen with paroxetine. In conclusion, SB-649915-B is acutely anxiolytic and reduces the latency to onset of anxiolytic behavior compared to paroxetine in the SI model.
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http://dx.doi.org/10.1038/sj.npp.1301341DOI Listing
October 2007

Simultaneous blockade of 5-HT1A/B receptors and 5-HT transporters results in acute increases in extracellular 5-HT in both rats and guinea pigs: in vivo characterization of the novel 5-HT1A/B receptor antagonist/5-HT transport inhibitor SB-649915-B.

Psychopharmacology (Berl) 2007 May 30;192(1):121-33. Epub 2007 Jan 30.

Psychiatry Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park (North), Harlow, Essex, CM19 5AW, UK.

Rationale: The delay in onset and treatment resistance of subpopulations of depressed patients to conventional serotonin reuptake inhibitors has lead to new drug development strategies to produce agents with improved antidepressant efficacy.

Objectives: We report the in vivo characterization of the novel 5-HT(1A/1B) autoreceptor antagonist/5-HT transporter inhibitor (6-[(1-{2-[(2-methyl-5-quinolinyl)oxy]ethyl}-4-piperidinyl)methyl]-2H-1,4-benzoxazin-3(4H)-one), SB-649915-B.

Materials And Methods: Ex vivo binding was used to ascertain 5-HT(1A) receptor and serotonin transporter occupancy. 8-OH-DPAT-induced hyperlocomotion and SKF-99101-induced elevation of seizure threshold were used as markers of central blockade of 5-HT(1A) and 5-HT(1B) receptors, respectively. In vivo electrophysiology in the rat dorsal raphe and microdialysis in freely moving guinea pigs and rats were used to evaluate the functional outcome of SB-649915-B.

Results: SB-649915-B (1-10 mg/kg p.o.) produced a dose-related inhibition of 5-HT(1A) receptor radioligand binding and inhibited ex vivo [(3)H]5-HT uptake in both guinea pig and rat cortex. SB-649915-B (0.1-10 mg/kg p.o.) reversed both 8-OH-DPAT-induced hyperlocomotor activity and SKF-99101-induced elevation of seizure threshold in the rat, demonstrating in vivo blockade of both 5-HT(1A) and 5-HT(1B) receptors, respectively. SB-649915-B (0.1-3 mg/kg i.v.) produced no change in raphe 5-HT neuronal cell firing per se but attenuated the inhibitory effect of 8-OH-DPAT. Acute administration of SB-649915-B resulted in increases (approximately two- to threefold) in extracellular 5-HT in the cortex of rats and the dentate gyrus and cortex of guinea pigs.

Conclusions: Based on these data, one may speculate that the 5-HT autoreceptor antagonist/5-HT transport inhibitor SB-649915-B will have therapeutic efficacy in the treatment of affective disorders with the potential for a faster onset of action compared to current selective serotonin reuptake inhibitors.
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http://dx.doi.org/10.1007/s00213-006-0691-xDOI Listing
May 2007

Studies towards the identification of a new generation of atypical antipsychotic agents.

Bioorg Med Chem Lett 2007 Jan 19;17(2):400-5. Epub 2006 Oct 19.

Psychiatry Centre of Excellence for Drug Discovery, New Frontiers Science Park, Harlow, Essex CM19 5AW, UK.

A rational structure-activity relationship study around compound (1) is reported. The lead optimisation programme led to the identification of sulfonamide (25), a molecule combining dopamine D2/D3 receptor antagonism with serotonin 5-HT2A, 5-HT2C, 5-HT6 receptor antagonism for an effective treatment of schizophrenia. Compound (25) was shown to possess the required in vivo activity with no EPS liability.
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http://dx.doi.org/10.1016/j.bmcl.2006.10.036DOI Listing
January 2007

SB-699551-A (3-cyclopentyl-N-[2-(dimethylamino)ethyl]-N-[(4'-{[(2-phenylethyl)amino]methyl}-4-biphenylyl)methyl]propanamide dihydrochloride), a novel 5-ht5A receptor-selective antagonist, enhances 5-HT neuronal function: Evidence for an autoreceptor role for the 5-ht5A receptor in guinea pig brain.

Neuropharmacology 2006 Sep 17;51(3):566-77. Epub 2006 Jul 17.

Psychiatry Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park (North), Harlow, Essex, UK.

This study utilised the selective 5-ht(5A) receptor antagonist, SB-699551-A (3-cyclopentyl-N-[2-(dimethylamino)ethyl]-N-[(4'-{[(2-phenylethyl)amino]methyl}-4-biphenylyl)methyl]propanamide dihydrochloride), to investigate 5-ht5A receptor function in guinea pig brain. SB-699551-A competitively antagonised 5-HT-stimulated [35S]GTPgammaS binding to membranes from human embryonic kidney (HEK293) cells transiently expressing the guinea pig 5-ht5A receptor (pA2 8.1+/-0.1) and displayed 100-fold selectivity versus the serotonin transporter and those 5-HT receptor subtypes (5-HT(1A/B/D), 5-HT2A/C and 5-HT7) reported to modulate central 5-HT neurotransmission in the guinea pig. In guinea pig dorsal raphe slices, SB-699551-A (1 microM) did not alter neuronal firing per se but attenuated the 5-CT-induced depression in serotonergic neuronal firing in a subpopulation of cells insensitive to the 5-HT1A receptor-selective antagonist WAY-100635 (100 nM). In contrast, SB-699551-A (100 or 300 nM) failed to affect both electrically-evoked 5-HT release and 5-CT-induced inhibition of evoked release measured using fast cyclic voltammetry in vitro. SB-699551-A (0.3, 1 and 3 mg/kg s.c.) did not modulate extracellular levels of 5-HT in the guinea pig frontal cortex in vivo. However, when administered in combination with WAY-100635 (0.3 mg/kg s.c.), SB-699551-A (0.3, 1 or 3 mg/kg s.c.) produced a significant increase in extracellular 5-HT levels. These studies provide evidence for an autoreceptor role for the 5-ht5A receptor in guinea pig brain.
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http://dx.doi.org/10.1016/j.neuropharm.2006.04.019DOI Listing
September 2006

Long-lasting changes in behavioural and neuroendocrine indices in the rat following neonatal maternal separation: gender-dependent effects.

Brain Res 2006 Jun 30;1097(1):123-32. Epub 2006 May 30.

Institute of Neuroscience, School of Biomedical Sciences, Queen's Medical Centre, University of Nottingham, NG7 2UH, Nottingham, UK.

Neonatal maternal separation (MS) has been used to model long-term changes in neurochemistry and behaviour associated with exposure to early-life stress. This study characterises changes in behavioural and neuroendocrine parameters following MS. On postnatal days (PND) 3-15, male and female Long-Evans rats underwent 3 h daily MS. Non-handled (NH) control offspring remained with the dams. Starting at PND 90, behaviour was assessed at weekly intervals in the elevated plus-maze, elevated T-maze, and locomotor activity boxes, and body weight monitored throughout. At the end of the study, adrenals were weighed and blood collected for analysis of plasma corticosterone and adrenocorticotropic hormone (ACTH) under basal conditions and following restraint stress. As adults, MS weighed more than NH animals. Activity on the open arms of the plus-maze was similar between MS and NH animals. In the T-maze, MS males had shorter emergence latencies than their NH counterparts. Spontaneous ambulation in a novel environment was significantly higher in MS than in NH animals, and males exhibited overall lower activity than females. Basal plasma corticosterone was lower in MS than in NH females, but no rearing condition difference was observed following restraint stress. Females had higher corticosterone and ACTH levels than males, whereas adrenal glands of MS animals weighed less than those of NH controls. The MS paradigm caused long-term gender dependent effects on behaviour and HPA axis status. The consistent gender differences confirm and expand existing results showing altered anxiety and stress reactivity in male and female rats.
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http://dx.doi.org/10.1016/j.brainres.2006.04.066DOI Listing
June 2006

Predicting drug efficacy for cognitive deficits in schizophrenia.

Schizophr Bull 2005 Oct 21;31(4):830-53. Epub 2005 Sep 21.

Psychiatry Centre of Excellence in Drug Discovery, GlaxoSmithKline plc., Essex, UK.

The purpose of this article is to discuss the prediction of cognitive enhancement in schizophrenia from preclinical data. Despite increasing focus on the significance of cognitive impairment in schizophrenia, the progress of novel treatments has been slow. Hyman and Fenton's identification of a "translational gap" between preclinical and clinical science underscores the need to revise preclinical, clinical, and regulatory practice. A review of the clinical literature identifies evidence for some cognitive benefits with current antipsychotics. The magnitude of these effects may, in some cases, be too small to be functionally relevant, and many studies are methodologically flawed, but the data might nevertheless allow translational links to be identified between clinical and preclinical studies. The literature is reviewed to determine if the cognitive signal reported in clinical studies is detectable in preclinical studies. The effects of antipsychotics on prepulse-inhibition deficits in animals is robust and demonstrates a reversal of drug-induced and developmentally induced deficits, although predictive links to the clinic are not well established. The preclinical literature on antipsychotic effects on attention, learning and memory, and recognition and executive function shows, with rare exceptions, impaired learning or task performance, rather than improvement. In general, therefore, preclinical studies have not detected the small pro-cognitive signal evident in the clinical literature. A number of factors may account for this. Effective closure of the translation gap for cognitive deficits in schizophrenia will require the design of a coherent preclinical strategy, and some of the potential elements of such a strategy are outlined and discussed.
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http://dx.doi.org/10.1093/schbul/sbi058DOI Listing
October 2005

Effect of vilazodone on 5-HT efflux and re-uptake in the guinea-pig dorsal raphe nucleus.

Eur J Pharmacol 2005 Jul;517(1-2):59-63

Psychiatry CEDD, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex, CM19 5AW, United Kingdom.

The effect of vilazodone, a putative selective serotonin re-uptake inhibitor (SSRI) with 5-HT (5-hydroxytryptamine)(1A) receptor partial agonist activity, was investigated on 5-HT efflux and 5-HT re-uptake half life in the guinea-pig dorsal raphe nucleus, using in vitro fast cyclic voltammetry. The SSRI, fluoxetine, significantly increased 5-HT efflux. In contrast, vilazodone had no effect on 5-HT efflux at 100 nM but significantly decreased 5-HT efflux at 1 microM. Co-perfusion of 8-OH-DPAT (+/-8-hydroxy-2-(di-n-propylamino)tetralin) with fluoxetine significantly attenuated the fluoxetine-induced increase in 5-HT efflux. Co-perfusion of WAY 100635 with vilazodone did not attenuate the effect of vilazodone alone. In addition, the re-uptake half life for 5-HT was significantly increased by both fluoxetine and vilazodone. In conclusion, we have demonstrated that vilazodone (100 nM, 1 microM), in the guinea-pig dorsal raphe nucleus, blocks the serotonin transporter but does not display 5-HT(1A) receptor agonism.
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http://dx.doi.org/10.1016/j.ejphar.2005.05.039DOI Listing
July 2005

The role of central dopamine D3 receptors in drug addiction: a review of pharmacological evidence.

Brain Res Brain Res Rev 2005 Jul;49(1):77-105

Centre of Excellence for Drug Discovery in Psychiatry, GlaxoSmithKline Pharmaceuticals, 37135 Verona, Italy.

The cDNA for the dopamine D3 receptor was isolated and characterized in 1990. Subsequent studies have indicated that D3 receptors, as well as D3 receptor mRNA, are primarily localized in limbic regions in mammals. This finding led to the postulate that D3 receptors may be involved in drug dependence and addiction. However, this hypothesis has been difficult to test due to the lack of compounds with high selectivity for central D3 receptors. The interpretation of results from studies using mixed D2/D3 agonists and/or antagonists is problematic because these agents have low selectivity for D3 over D2 receptors and it is likely that their actions are primarily related to D2 receptor antagonism and possibly interaction with other neurotransmitter receptors. Currently, with the synthesis and characterization of new highly selective D3 receptor antagonists such as SB-277011-A this difficulty has been surmounted. The purpose of the present article is to review, for the first time, the effects of various putative D3 receptor selective compounds in animal models of drug dependence and addiction. The results obtained with highly selective D3 receptor antagonists such as SB-277011-A, SB-414796, and NGB-2904 indicate that central D3 receptors may play an important role in drug-induced reward, drug-taking, and cue-, drug-, and stress-induced reinstatement of drug-seeking behavior. Provided these results can be extrapolated to human drug addicts, they suggest that selective DA D3 receptor antagonists may prove effective as potential pharmacotherapeutic agents to manage drug dependence and addiction.
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http://dx.doi.org/10.1016/j.brainresrev.2004.12.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3732040PMC
July 2005

5-HT6 receptor antagonists improve performance in an attentional set shifting task in rats.

Psychopharmacology (Berl) 2005 Sep 14;181(2):253-9. Epub 2005 Oct 14.

Schizophrenia and Bipolar Disorders Research, Psychiatry CEDD, Harlow, Essex, UK,

Rationale And Objective: Performance on the Wisconsin Card Sorting Test (WCST), which requires patients to 'shift attention' between stimulus dimensions (sorting categories), is impaired in diseases such as schizophrenia. The rat attentional set shifting task is an analogue of the WCST. Given that 5-HT(6) receptor antagonists improve cognitive performance and influence cortical neurochemistry in rats, the present study investigated the effects of 5-HT(6) receptor antagonists upon attentional set shifting in rats.

Methods: Rats were tested in this paradigm following sub-chronic SB-399885-T or SB-271046-A (both 10 mg kg(-1) bid, p.o. for 8 days prior to testing and either 4 or 2 h prior to testing on day 9, respectively). Rats were trained to dig in baited bowls for a food reward and to discriminate based on odour or digging media (Habituation, day 8). In a single session (day 9), rats performed a series of discriminations, including reversals (REV), intra-dimensional (ID) and extra-dimensional (ED) shifts.

Results: Neither compound altered performance during Habituation. On the test day, both SB-399885-T and SB-271046-A reduced the total trials to reach criterion and the total errors made when data were collapsed across all discriminations (P<0.05-0.01). Further, both compounds significantly reduced the trials to criterion for REV-1 (P<0.05-0.01) and abolished the ID/ED shift. SB-399885-T, but not SB-271046-A, reduced trials required to complete the ED shift (P<0.05) and the number of errors made during completion of the ID (P<0.05) and ED shifts (P<0.01).

Conclusion: 5-HT(6) receptor antagonists improved performance in the attentional set shifting task and may have therapeutic potential in the treatment of disorders where cognitive deficits are a feature, including schizophrenia.
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http://dx.doi.org/10.1007/s00213-005-2261-zDOI Listing
September 2005

Novel pharmacotherapeutic approaches for the treatment of drug addiction and craving.

Curr Opin Pharmacol 2005 Feb;5(1):107-18

Department of Biology, Centre of Excellence for Drug Discovery in Psychiatry, GlaxoSmithKline Pharmaceuticals, 37135 Verona, Italy.

Pharmacological agents have shown limited efficacy and consistency in the treatment of drug addiction. Hence, the development of new medications with improved long-term efficacy and reduced side effects should be given a high priority given the costs to society associated with drug abuse and drug-related pathologies. Neurochemical systems can be significantly altered by repeated exposure to drugs of abuse. These long-term molecular and neurochemical changes might, in turn, explain the core features of addiction--the compulsive seeking and taking of the drug--as well as the risk of relapse.
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http://dx.doi.org/10.1016/j.coph.2004.08.013DOI Listing
February 2005

Localisation of NMU1R and NMU2R in human and rat central nervous system and effects of neuromedin-U following central administration in rats.

Psychopharmacology (Berl) 2004 Dec 16;177(1-2):1-14. Epub 2004 Jun 16.

Psychiatry Centre of Excellence for Drug Discovery, GlaxoSmithKline plc, New Frontiers Science Park, Third Avenue, Harlow, CM19 5AW, Essex, United Kingdom.

Rationale: Neuromedin-U (NmU) is an agonist at NMU1R and NMU2R. The brain distribution of NmU and its receptors, in particular NMU2R, suggests widespread central roles for NmU. In agreement, centrally administered NmU affects feeding behaviour, energy expenditure and pituitary output. Further central nervous system (CNS) roles for NmU warrant investigation.

Objectives: To investigate the CNS role of NmU by mapping NMU1R and NMU2R mRNA and measuring the behavioural, endocrine, neurochemical and c-fos response to intracerebroventricular (i.c.v.) NmU.

Methods: Binding affinity and functional potency of rat NmU was determined at human NMU1R and NMU2R. Expression of NMU1R and NMU2R mRNA in rat and human tissue was determined using semi-quantitative reverse-transcription polymerase chain reaction. In in-vivo studies, NmU was administered i.c.v. to male Sprague-Dawley rats, and changes in grooming, motor activity and pre-pulse inhibition (PPI) were assessed. In further studies, plasma endocrine hormones, [DOPAC + HVA]/[dopamine] and [5-HIAA]/[5-HT] ratios and levels of Fos-like immunoreactivity (FLI) were measured 20 min post-NmU (i.c.v.).

Results: NmU bound to NMU1R ( K(I), 0.11+/-0.02 nM) and NMU2R ( K(I), 0.21+/-0.05 nM) with equal affinity and was equally active at NMU1R (EC(50), 1.25+/-0.05 nM) and NMU2R (EC(50), 1.10+/-0.20 nM) in a functional assay. NMU2R mRNA expression was found at the highest levels in the CNS regions of both rat and human tissues. NMU1R mRNA expression was restricted to the periphery of both species with the exception of the rat amygdala. NmU caused a marked increase in grooming and motor activity but did not affect PPI. Further, NmU decreased plasma prolactin but did not affect levels of corticosterone, luteinising hormone or thyroid stimulating hormone. NmU elevated levels of 5-HT in the frontal cortex and hypothalamus, with decreased levels of its metabolites in the hippocampus and hypothalamus, but did not affect dopamine function. NmU markedly increased FLI in the nucleus accumbens, frontal cortex and central amygdala.

Conclusions: These data provide further evidence for widespread roles for NmU and its receptors in the brain.
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http://dx.doi.org/10.1007/s00213-004-1918-3DOI Listing
December 2004

Urotensin-II, a neuropeptide ligand for GPR14, induces c-fos in the rat brain.

Eur J Pharmacol 2004 Jun;493(1-3):95-8

Psychiatry CEDD, GlaxoSmithKline, Third Avenue, Harlow, Essex CM19 5AW, UK.

The vasoactive peptide urotensin-II and its receptor, GPR14 (now known as UT receptor), are localised in the mammalian central nervous system. Accordingly, various centrally mediated effects of urotensin-II on behaviour, neuroendocrine hormones and neurochemistry have been described. To investigate neuroanatomical substrates for the central actions of urotensin-II, expression of the immediate early gene c-fos was examined following intracerebroventricular administration to rats. Urotensin-II increased Fos expression in the cingulate cortex and periaqueductal grey, suggesting important central roles for urotensin-II and its receptor.
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http://dx.doi.org/10.1016/j.ejphar.2004.04.009DOI Listing
June 2004

Blockade of mesolimbic dopamine D3 receptors inhibits stress-induced reinstatement of cocaine-seeking in rats.

Psychopharmacology (Berl) 2004 Oct 9;176(1):57-65. Epub 2004 Apr 9.

Neuropsychopharmacology Section, Intramural Research Program, Department of Health and Human Services, National Institute on Drug Abuse, National Institutes of Health, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA.

Rationale: The dopamine (DA) D3 receptor is preferentially expressed in the mesolimbic system. We have previously shown that selective D3 receptor blockade by the novel D3 antagonist SB-277011A inhibits cocaine's reinforcing action and cocaine-induced reinstatement of cocaine-seeking behavior.

Objective: In the present study, we investigated whether SB-277011A similarly inhibits stress-induced reinstatement of cocaine-seeking behavior.

Methods: Rats were allowed to self-administer cocaine (0.5 mg/kg per infusion, 3 h per session) for 10-14 days, followed by a once-daily extinction session for 7-14 days during which saline was substituted for cocaine. Extinction criteria were fewer than ten lever-presses per 3-h session for at least 3 consecutive days. After cocaine-seeking behavior was extinguished, each animal was tested twice for footshock-stress-induced reinstatement, once with vehicle (25% hydroxypropyl-beta-cyclodextrin) and once with one of three doses of SB-277011A in counterbalanced fashion.

Results: During the last 3 days of cocaine self-administration (SA), active lever-presses were approximately 100 per session under fixed-ratio 2 reinforcement (approximately 25 mg/kg cocaine per session). After extinction, intermittent footshock (10 min, 0.5 mA, 0.5 s on with a mean inter-shock interval of 40 s) robustly reinstated the cocaine-seeking behavior (8.4+/-3.6 active lever-presses in last extinction session to 35.3+/-5.2 in animals after footshock stress). Intraperitoneal (i.p.) injections of SB-277011A (3, 6, and 12 mg/kg) dose-dependently blocked stress-induced reinstatement of cocaine-seeking. Reinstatement was also blocked by microinjections of SB-277011A (1.5 microg/0.5 microl per side) bilaterally into the nucleus accumbens, but not into the dorsal striatum.

Conclusions: The mesolimic DA D3 receptor plays an important role in mediating stress-induced reinstatement.
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http://dx.doi.org/10.1007/s00213-004-1858-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3726040PMC
October 2004

5-HT7 receptors.

Curr Drug Targets CNS Neurol Disord 2004 Feb;3(1):81-90

Department of Biology, Psychiatry Centre of Excellence for Drug Discovery, GlaxoSmithKline, Harlow, Essex, UK.

Following the cloning of the 5-HT(7) receptor in 1993, studies to investigate 5-HT(7) receptor function in native tissues focused on identifying functional correlates that matched the pharmacological profile determined for the cloned receptor. Studies in peripheral tissues established that the 5-HT(7) receptor mediates the relaxation of smooth muscle, including the gastrointestinal tract and cardiovascular systems. Although a number of studies provided preliminary evidence for a role for the 5-HT(7) receptor in the circadian pacemaker function of the suprachiasmatic nucleus (SCN), additional studies to investigate 5-HT(7) receptor function in other brain regions have, until recently, been hindered by the absence of 5-HT(7) receptor-selective ligands. More recently, a number of 5-HT(7) receptor-selective antagonists including, SB-269970-A and SB-656104-A have been developed. Studies utilising these compounds suggest that the 5-HT(7) receptor modulates neuronal function in a number of brain areas including the hippocampus and thalamus. In turn, these findings suggest that 5-HT(7) receptor-selective ligands might prove therapeutically useful for the treatment of psychiatric disorders. In this respect there is increasing evidence to suggest that the 5-HT(7) receptor plays a role in the control of both circadian rhythms and sleep and might therefore represent a therapeutic target for the treatment of those disorders in which disturbances in circadian rhythms and sleep architecture are thought to be contributory factors. Furthermore, there is evidence to suggest that the receptor may play a role in other CNS disorders including, anxiety, cognitive disturbances and also migraine probably via both peripheral and central mechanisms. Although further studies are required to confirm the potential role of the receptor in such disorders, findings to date suggest there are exciting opportunities for the development of novel therapeutic agents acting either selectively at the 5-HT(7) receptor or whose profile of action includes an interaction with this receptor.
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http://dx.doi.org/10.2174/1568007043482633DOI Listing
February 2004

Effect of the acute and chronic administration of the selective 5-HT6 receptor antagonist SB-271046 on the activity of midbrain dopamine neurons in rats: an in vivo electrophysiological study.

Synapse 2004 Apr;52(1):20-8

Department of Psychiatry and Neurology, Hamamatsu University School of Medicine, Hamamatsu, 431-3192 Shizuoka, Japan.

This study examined the effect of the acute and repeated per os (p.o.) administration of the selective 5-HT(6) receptor antagonist SB-271046, on the number, as well as the firing pattern of spontaneously active dopamine (DA) neurons in the rat substantia nigra pars compacta (SNC) and ventral tegmental area (VTA) in anesthetized male Sprague-Dawley rats. This was accomplished using the technique of extracellular in vivo electrophysiology. A single p.o. administration of either 1, 3, or 10 mg/kg of SB-271046 did not significantly alter the number of spontaneously active SNC DA neurons per stereotaxic electrode tract compared to vehicle-treated animals. The acute administration of either 1 or 3 mg/kg of SB-271046 did not significantly alter the number of spontaneously active VTA DA neurons. In contrast, a significant decrease in the number of spontaneously active VTA DA neurons was observed after a single administration of 10 mg/kg of SB-271046 compared to vehicle-treated animals. The acute p.o. administration of SB-271046 significantly altered the firing pattern parameters of all (bursting + nonbursting DA neurons) DA neurons, particularly those in the VTA, compared to vehicle-treated animals. The repeated p.o. administration (once per day for 21 days) of 1, 3, or 10 mg/kg of SB-271046 did not significantly alter the number of spontaneously active VTA DA neurons compared to vehicle-treated animals. The repeated administration of 3 or 10 mg/kg of SB-271046 significantly increased the number of spontaneously active SNC DA neurons compared to vehicle controls. Overall, the repeated administration of SB-271046 had relatively little effect on the firing pattern of midbrain DA neurons. The results obtained following the chronic administration of SB-271046 show that this compound has a profile different from that of typical or atypical antipsychotic drugs in this model. Clinical studies are required to understand what role 5-HT(6) receptor blockade might eventually play in the treatment of schizophrenia.
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http://dx.doi.org/10.1002/syn.20002DOI Listing
April 2004

5-HT6 receptor antagonist SB-271046 enhances extracellular levels of monoamines in the rat medial prefrontal cortex.

Synapse 2004 Feb;51(2):158-64

Centre of Excellence for Drug Discovery in Psychiatry, Department of Biology, GlaxoSmithKline Pharmaceuticals, 37135 Verona, Italy, and Harlow, CM19 5AW, UK.

The present study investigated the neurochemical effects of the selective 5-HT(6) receptor antagonist SB-271046 in the rat medial prefrontal cortex (mPFC). The effect of SB-271046 on extracellular levels of dopamine (DA), norepinephrine (NE), and serotonin (5-HT) in the mPFC was examined using in vivo microdialysis in the freely moving rat. SB-271046 (10 mg/kg, p.o.) produced a significant increase in extracellular levels of both DA and NE without altering 5-HT neurotransmission. These results further support the rationale for the use of 5-HT(6) receptor antagonists in the treatment of cognitive dysfunction associated with psychiatric diseases.
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http://dx.doi.org/10.1002/syn.10288DOI Listing
February 2004

Design and synthesis of trans-3-(2-(4-((3-(3-(5-methyl-1,2,4-oxadiazolyl))- phenyl)carboxamido)cyclohexyl)ethyl)-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SB-414796): a potent and selective dopamine D3 receptor antagonist.

J Med Chem 2003 11;46(23):4952-64

GlaxoSmithKline Pharmaceuticals, New Frontiers Science Park, Third Avenue, Harlow, Essex, CM19 5AW, UK.

At their clinical doses, current antipsychotic agents share the property of both dopamine D(2) and D(3) receptor blockade. However, a major disadvantage of many current medications are the observed extrapyramidal side-effects (EPS), postulated to arise from D(2) receptor antagonism. Consequently, a selective dopamine D(3) receptor antagonist could offer an attractive antipsychotic therapy, devoid of the unwanted EPS. Using SAR information gained in two previously reported series of potent and selective D(3) receptor antagonists, as exemplified by the 2,3,4,5-tetrahydro-1H-3-benzazepine 10 and the 2,3-dihydro-1H-isoindoline 11, a range of 7-sulfonyloxy- and 7-sulfonylbenzazepines has been prepared. Compounds of this type combined a high level of D(3) affinity and selectivity vs D(2) with an excellent pharmacokinetic profile in the rat. Subsequent optimization of this series to improve selectivity over a range of receptors and reduce cytochrome P450 inhibitory potential gave trans-3-(2-(4-((3-(3-(5-methyl-1,2,4-oxidiazolyl))phenyl)carboxamido)cyclohexyl)ethyl)-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine (58, SB-414796). This compound is a potent and selective dopamine D(3) receptor antagonist with high oral bioavailability and is CNS penetrant in the rat. Subsequent evaluation in the rat has shown that 58 preferentially reduces firing of dopaminergic cells in the ventral tegmental area (A10) compared to the substantia nigra (A9), an observation consistent with a prediction for atypical antipsychotic efficacy. In a separate study, 58 has been shown to block expression of the conditioned place preference (CPP) response to cocaine in male rats, suggesting that it may also have a role in the treatment of cue-induced relapse in drug-free cocaine addicts.
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http://dx.doi.org/10.1021/jm030817dDOI Listing
November 2003

The 5-HT(6) receptor antagonist SB-271046 reverses scopolamine-disrupted consolidation of a passive avoidance task and ameliorates spatial task deficits in aged rats.

Neuropsychopharmacology 2004 Jan;29(1):93-100

Department of Pharmacology, Conway Institute, University College Dublin, Belfield, Ireland.

The highly potent and selective 5-HT(6) receptor antagonist SB-271046 [5-chloro-N-(4-methoxy-3-piperazin-1-yl-phenyl)-3-methyl-2-benzothiophenesulfonamide] has previously been demonstrated to improve retention significantly in a spatial water maze paradigm in adult rats. However, SB-271046 did not have any effect on task acquisition. As these apparently contradictory findings may be reconciled by a prime influence of SB-271046 on memory consolidation, the ability of this compound to reverse the discrete temporal action of a cholinergic antagonist in the 6-h period following passive avoidance training was investigated. SB-271046, given orally, by gavage, 30 min prior to training Wistar rats in a step-through, light-dark passive avoidance task, was found to reverse significantly the amnesia produced by administering scopolamine (0.8 mg/kg, intraperitoneal) in the 6-h post-training period. The effect was dose-dependent over a range of 3-20 mg/kg. Further, we investigated the cognition-enhancing effects of chronic SB-271046 administration (10 or 20 mg/kg/day; 40 days) on the acquisition and consolidation of a water maze spatial learning task in a population of 20-month-old Wistar rats with age-related learning deficits. Drug treatment progressively and significantly decreased platform swim angle and escape latencies over the five sequential trials on four consecutive daily sessions compared to vehicle-treated controls. SB-271046 also improved task recall as measured by significant increases in the searching of the target quadrant on post-training days 1 and 3, when the animals would have been substantially drug-free. This significant improvement of task recall suggests SB-271046, in addition to inducing symptomatic cognition-enhancing actions, also attenuates age-related decline in neural function.
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http://dx.doi.org/10.1038/sj.npp.1300332DOI Listing
January 2004