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Dive into the research topics where Claire M. Scott is active.

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Featured researches published by Claire M. Scott.


British Journal of Pharmacology | 2004

Characterisation of the binding of [3H]-SB-674042, a novel nonpeptide antagonist, to the human orexin-1 receptor

Christopher J. Langmead; Jeffrey C. Jerman; Stephen J Brough; Claire M. Scott; Rod A. Porter; Hugh J. Herdon

This study characterises the binding of a novel nonpeptide antagonist radioligand, [3H]SB‐674042 (1‐(5‐(2‐fluoro‐phenyl)‐2‐methyl‐thiazol‐4‐yl)‐1‐((S)‐2‐(5‐phenyl‐(1,3,4)oxadiazol‐2‐ylmethyl)‐pyrrolidin‐1‐yl)‐methanone), to the human orexin‐1 (OX1) receptor stably expressed in Chinese hamster ovary (CHO) cells in both a whole cell assay and in a cell membrane‐based scintillation proximity assay (SPA) format. Specific binding of [3H]SB‐674042 was saturable in both whole cell and membrane formats. Analyses suggested a single high‐affinity site, with Kd values of 3.76±0.45 and 5.03±0.31 nM, and corresponding Bmax values of 30.8±1.8 and 34.4±2.0 pmol mg protein−1, in whole cell and membrane formats, respectively. Kinetic studies yielded similar Kd values. Competition studies in whole cells revealed that the native orexin peptides display a low affinity for the OX1 receptor, with orexin‐A displaying a ∼five‐fold higher affinity than orexin‐B (Ki values of 318±158 and 1516±597 nM, respectively). SB‐334867, SB‐408124 (1‐(6,8‐difluoro‐2‐methyl‐quinolin‐4‐yl)‐3‐(4‐dimethylamino‐phenyl)‐urea) and SB‐410220 (1‐(5,8‐difluoro‐quinolin‐4‐yl)‐3‐(4‐dimethylamino‐phenyl)‐urea) all displayed high affinity for the OX1 receptor in both whole cell (Ki values 99±18, 57±8.3 and 19±4.5 nM, respectively) and membrane (Ki values 38±3.6, 27±4.1 and 4.5±0.2 nM, respectively) formats. Calcium mobilisation studies showed that SB‐334867, SB‐408124 and SB‐410220 are all functional antagonists of the OX1 receptor, with potencies in line with their affinities, as measured in the radioligand binding assays, and with approximately 50‐fold selectivity over the orexin‐2 receptor. These studies indicate that [3H]SB‐674042 is a specific, high‐affinity radioligand for the OX1 receptor. The availability of this radioligand will be a valuable tool with which to investigate the physiological functions of OX1 receptors.


British Journal of Pharmacology | 2003

SB-656104-A, a novel selective 5-HT7 receptor antagonist, modulates REM sleep in rats

David R. Thomas; Sergio Melotto; Mario Massagrande; Andrew Derrick GlaxoSmithKline Gribble; Phillip Jeffrey; Alexander J. Stevens; Nigel J. Deeks; Peter Eddershaw; Susan H Fenwick; Graham J. Riley; Tania O. Stean; Claire M. Scott; Matthew Hill; Derek N. Middlemiss; Jim J. Hagan; Gary W. Price; Ian Thomson Forbes

(6‐((R)‐2‐{2‐[4‐(4‐Chloro‐phenoxy)‐piperidin‐1‐yl]‐ethyl}‐pyrrolidine‐1‐sulphonyl)‐1H‐indole hydrochloride) (SB‐656104‐A), a novel 5‐hydroxytryptamine (5‐HT7) receptor antagonist, potently inhibited [3H]‐SB‐269970 binding to the human cloned 5‐HT7(a) (pKi 8.7±0.1) and 5‐HT7(b) (pKi 8.5±0.2) receptor variants and the rat native receptor (pKi 8.8±0.2). The compound displayed at least 30‐fold selectivity for the human 5‐HT7(a) receptor versus other human cloned 5‐HT receptors apart from the 5‐HT1D receptor (∼10‐fold selective). SB‐656104‐A antagonised competitively the 5‐carboxamidotryptamine (5‐CT)‐induced accumulation of cyclic AMP in h5‐HT7(a)/HEK293 cells with a pA2 of 8.5. Following a constant rate iv infusion to steady state in rats, SB‐656104 had a blood clearance (CLb) of 58±6 ml min−1 kg−1 and was CNS penetrant with a steady‐state brain : blood ratio of 0.9 : 1. Following i.p. administration to rats (10 mg kg−1), the compound displayed a t1/2 of 1.4 h with mean brain and blood concentrations (at 1 h after dosing) of 0.80 and 1.0 μM, respectively. SB‐656104‐A produced a significant reversal of the 5‐CT‐induced hypothermic effect in guinea pigs, a pharmacodynamic model of 5‐HT7 receptor interaction in vivo (ED50 2 mg kg−1). SB‐656104‐A, administered to rats at the beginning of the sleep period (CT 0), significantly increased the latency to onset of rapid eye movement (REM) sleep at 30 mg kg−1 i.p. (+93%) and reduced the total amount of REM sleep at 10 and 30 mg kg−1 i.p. with no significant effect on the latency to, or amount of, non‐REM sleep. SB‐269970‐A produced qualitatively similar effects in the same study. In summary, SB‐656104‐A is a novel 5‐HT7 receptor antagonist which has been utilised in the present study to provide further evidence for a role for 5‐HT7 receptors in the modulation of REM sleep.


British Journal of Pharmacology | 1998

SB-224289–a novel selective (human) 5-HT1B receptor antagonist with negative intrinsic activity

J V Selkirk; Claire M. Scott; M Ho; M J Burton; Jeannette M. Watson; L M Gaster; L Collin; Brian J. Jones; Derek N. Middlemiss; Gary W. Price

1 Human 5‐HT1B (h5‐HT1B) and human 5‐HT1D (h5‐HT1D) receptors show remarkably similar pharmacology with few compounds discriminating the receptors. We report here on a novel compound, SB‐224289 (1′‐Methyl‐5‐[[2′‐methyl‐4′‐(5‐methyl‐1,2,4‐oxadiazol‐3‐yl)biphenyl‐4‐yl]carbonyl]‐2,3,6,7‐tetrahydrospiro [furo [2,3‐f]indole‐3,4′‐piperidine] oxalate), which has high affinity for h5‐HT1B receptors (pK1=8.16±0.06) and displays over 75 fold selectivity for the h5‐HT1B receptor over all other 5‐HT receptors including the h5‐HT1D receptor and all other receptors tested thus far. 2 Functional activity of SB‐224289 was measured in a [35S]GTPγS binding assay on recombinant h5‐HT1B and h5‐HT1D receptors expressed in Chinese Hamster Ovary (CHO) cells. SB‐224289 displayed negative intrinsic activity at both receptors with higher potency at h5‐HT1B receptors. SB‐224289 caused a rightward shift of agonist concentration response curves consistent with competitive antagonism and generated affinities comparable with those obtained from competition radioligand receptor binding studies. 3 SB‐224289 potentiated [3H]5‐HT release from electrically stimulated guinea‐pig cerebral cortical slices to the same extent as as the non‐selective 5‐HT1 antagonist methiothepin. SB‐224289 also fully reversed the inhibitory effect of exogenously superfused 5‐HT on electrically stimulated release. 4 Using SB‐224289 as a tool compound, we confirm that in guinea‐pig cerebral cortex the terminal 5‐HT autoreceptor is of the 5‐HT1B subtype.


British Journal of Pharmacology | 2000

5-HT1A receptor agonist-antagonist binding affinity difference as a measure of intrinsic activity in recombinant and native tissue systems

Jeannette M. Watson; L Collin; M Ho; Graham J. Riley; Claire M. Scott; J V Selkirk; Gary W. Price

It has been reported that radiolabelled agonist : antagonist binding affinity ratios can predict functional efficacy at several different receptors. This study investigates whether this prediction is true for recombinant and native tissue 5‐HT1A receptors. Saturation studies using [3H]‐8‐OH‐DPAT and [3H]‐MPPF revealed a single, high affinity site (KD∼1 nM) in HEK293 cells expressing human 5‐HT1A receptors and rat cortex. In recombinant cells, [3H]‐MPPF labelled 3–4 fold more sites than [3H]‐8‐OH‐DPAT suggesting the presence of more than one affinity state of the receptor. [3H]‐Spiperone labelled a single, lower affinity site in HEK293 cells expressing h5‐HT1A receptors but did not bind to native tissue 5‐HT1A receptors. These data suggest that, in transfected HEK293 cells, human 5‐HT1A receptors exist in different affinity states but in native rat cortical tissue the majority of receptors appear to exist in the high agonist affinity state. Receptor agonists inhibited [3H]‐MPPF binding from recombinant 5‐HT1A receptors in a biphasic manner, whereas antagonists and partial agonists gave monophasic inhibition curves. All compounds displaced [3H]‐8‐OH‐DPAT and [3H]‐spiperone binding in a monophasic manner. In rat cortex, all compounds displaced [3H]‐MPPF and [3H]‐8‐OH‐DPAT in a monophasic manner. Functional evaluation of compounds, using [35S]‐GTPγS binding, produced a range of intrinsic activities from full agonism, displayed by 5‐HT and 5‐CT to inverse agonism displayed by spiperone. [3H]‐8‐OH‐DPAT : [3H]‐MPPF pKi difference correlated well with functional intrinsic activity (r=0.86) as did [3H]‐8‐OH‐DPAT : [3H]‐spiperone pKi difference with functional intrinsic activity (r=0.96). Thus agonist : antagonist binding affinity differences may be used to predict functional efficacy at human 5‐HT1A receptors expressed in HEK293 cells where both high and low agonist affinity states are present but not at native rat cortical 5‐HT1A receptors in which only the high agonist affinity state was detectable.


Neuropsychopharmacology | 2008

In vitro and in vivo characterization of the non-peptide NK3 receptor antagonist SB-223412 (talnetant): potential therapeutic utility in the treatment of schizophrenia.

Lee A. Dawson; Katherine J. Cato; Claire M. Scott; Jeannette M. Watson; Martyn D. Wood; Richard R. Foxton; Raúl de la Flor; Gareth A. Jones; James N.C. Kew; Jane E. Cluderay; Eric Southam; Graham Murkitt; Jane Gartlon; Darrel J. Pemberton; Declan N.C. Jones; Ceri H. Davies; Jim J. Hagan

Neurokinin-3 (NK3) receptors are concentrated in forebrain and basal ganglia structures within the mammalian CNS. This distribution, together with the modulatory influence of NK3 receptors on monoaminergic neurotransmission, has led to the hypothesis that NK3 receptor antagonists may have therapeutic efficacy in the treatment of psychiatric disorders. Here we describe the in vitro and in vivo characterization of the highly selective NK3 receptor antagonist talnetant (SB-223412). Talnetant has high affinity for recombinant human NK3 receptors (pKi 8.7) and demonstrates selectivity over other neurokinin receptors (pKi NK2=6.6 and NK1<4). In native tissue-binding studies, talnetant displayed high affinity for the guinea pig NK3 receptor (pKi 8.5). Functionally, talnetant competitively antagonized neurokinin B (NKB)-induced responses at the human recombinant receptor in both calcium and phosphoinositol second messenger assay systems (pA2 of 8.1 and 7.7, respectively). In guinea pig brain slices, talnetant antagonized NKB-induced increases in neuronal firing in the medial habenula (pKB=7.9) and senktide-induced increases in neuronal firing in the substantia nigra pars compacta (pKB=7.7) with no diminution of maximal agonist efficacy, suggesting competitive antagonism at native NK3 receptors. Talnetant (3–30 mg/kg i.p.) significantly attenuated senktide-induced ‘wet dog shake’ behaviors in the guinea pig in a dose-dependent manner. Microdialysis studies demonstrated that acute administration of talnetant (30 mg/kg i.p.) produced significant increases in extracellular dopamine and norepinephrine in the medial prefrontal cortex and attenuated haloperidol-induced increases in nucleus accumbens dopamine levels in the freely moving guinea pigs. Taken together, these data demonstrate that talnetant is a selective, competitive, brain-penetrant NK3 receptor antagonist with the ability to modulate mesolimbic and mesocortical dopaminergic neurotransmission and hence support its potential therapeutic utility in the treatment of schizophrenia.


Cns & Neurological Disorders-drug Targets | 2006

Pharmacological Profile of Antipsychotics at Monoamine Receptors: Atypicality Beyond 5-HT2A Receptor Blockade

Martyn D. Wood; Claire M. Scott; Kirsten Clarke; Katherine J. Cato; Nisha Patel; Jennie Heath; Angela Worby; Laurie J. Gordon; Lorraine Campbell; Graham J. Riley; Ceri H. Davies; Andrew Derrick GlaxoSmithKline Gribble; Declan N.C. Jones

Antipsychotic drugs (APD) are widely prescribed for the treatment of schizophrenia. The APD are differentiated into typical and atypical based on the lower incidence of extra-pyramidal side-effects associated with the newer atypical APD. It was suggested that atypicality may arise from an interaction with the 5-hydroxytryptamine (5-HT)(2) receptor and specifically on the 5-HT(2):dopamine D(2) affinity ratio. It is now realised that multiple subtypes of these receptors exist and that in addition, atypical APD interact with many monoamine receptors. The aim of the present study was to characterise the interaction of APD with a variety of monoamine receptors in terms of both affinity and efficacy. The data produced has highlighted that the atypical profile of APD such as olanzapine and clozapine may reflect antagonism of the 5-HT(2A) and 5-HT(2C) receptors, whilst that of, ziprasidone and quetiapine may reflect partial agonist activity at the 5-HT(1A) receptor, and that of aripiprazole may reflect partial agonist activity at the 5-HT(1A) receptor as well as is its claimed partial agonist activity at the dopamine D(2) receptor.


British Journal of Pharmacology | 2001

SB-272183, a selective 5-HT1A, 5-HT1B and 5-HT1D receptor antagonist in native tissue

Jeannette M. Watson; Claire Roberts; Claire M. Scott; I Kendall; L Collin; N C Day; Mark Harries; Ellen M. Soffin; Ceri H. Davies; Andrew D. Randall; T Heightman; L M Gaster; Paul Adrian Wyman; C Parker; Gary W. Price; Derek N. Middlemiss

A novel compound, SB‐272183 (5‐Chloro‐2, 3‐dihydro‐6‐[4‐methylpiperazin‐1‐yl]‐1[4‐pyridin‐4‐yl]napth‐1‐ylaminocarbonyl]‐1H‐indole), has been shown to have high affinity for human 5‐HT1A, 5‐HT1B and 5‐HT1D receptors with pKi values of 8.0, 8.1 and 8.7 respectively and is at least 30 fold selective over a range of other receptors. [35S]‐GTPγS binding studies showed that SB‐272183 acts as a partial agonist at human recombinant 5‐HT1A, 5‐HT1B and 5‐HT1D receptors with intrinsic activities of 0.4, 0.4 and 0.8 respectively, compared to 5‐HT. SB‐272183 inhibited 5‐HT‐induced stimulation of [35S]‐GTPγS binding at human 5‐HT1A and 5‐HT1B receptors to give pA2 values of 8.2 and 8.5 respectively. However, from [35S]‐GTPγS autoradiographic studies in rat and human dorsal raphe nucleus, SB‐272183 did not display intrinsic activity up to 10 μM but did block 5‐HT‐induced stimulation of [35S]‐GTPγS binding. From electrophysiological studies in rat raphe slices in vitro, SB‐272183 did not effect cell firing rate up to 1 μM but was able to attenuate (+)8‐OH‐DPAT‐induced inhibition of cell firing to give an apparent pKb of 7.1. SB‐272183 potentiated electrically‐stimulated [3H]‐5‐HT release from rat and guinea‐pig cortical slices at 100 and 1000 nM, similar to results previously obtained with the 5‐HT1B and 5‐HT1D receptor antagonist, GR127935. Fast cyclic voltammetry studies in rat dorsal raphe nucleus showed that SB‐272183 could block sumatriptan‐induced inhibition of 5‐HT efflux, with an apparent pKb of 7.2, but did not effect basal efflux up to 1 μM. These studies show that, in vitro, SB‐272183 acts as an antagonist at native tissue 5‐HT1A, 5‐HT1B and 5‐HT1D receptors.


Bioorganic & Medicinal Chemistry Letters | 2008

Novel 5-HT1A/1B/1D receptors antagonists with potent 5-HT reuptake inhibitory activity

Halina T Serafinowska; Frank E. Blaney; Peter J. Lovell; Giancarlo Merlo; Claire M. Scott; Paul W. Smith; Kathryn R. Starr; Jeannette M. Watson

Novel 2-methyl-5-quinolinyl-1-piperazinylalkyl-3,4-dihydro-2H-1,4-benzoxazin-3-ones showing high affinities for the 5-HT(1A/1B/1D) receptors coupled with potent 5-HT reuptake inhibitory activity have been discovered. This is the first report describing docking of the lead compound 6-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}-2H-1,4-benzoxazin-3(4H)-one 1, into a model of the 5-HT transporter and the 5-HT(1A) receptor model.


Journal of Medicinal Chemistry | 2008

Discovery of potent, orally bioavailable, selective 5-HT1A/B/D receptor antagonists

Simon E. Ward; Peter Eddershaw; Claire M. Scott; Laurie J. Gordon; Peter J. Lovell; Susan H. Moore; Paul W. Smith; Kathryn R. Starr; Kevin M. Thewlis; Jeannette M. Watson

5-HT1 receptor antagonists have been discovered with good selectivity over the 5-HT transporter. This is the first report of highly potent, selective ligands for the 5-HT1A/B/D receptors with low intrinsic activity, which represent a useful set of molecules for further understanding the roles of the 5-HT1 receptor subtypes and providing new approaches for the treatment of depression.


Neuropharmacology | 2006

SB-616234-A (1-[6-(cis-3,5-dimethylpiperazin-1-yl)-2,3-dihydro-5-methoxyindol-1-yl]-1-[2′methyl-4′-(5-methyl-1,2,3-oxadiazol-3-yl)biphenyl-4-yl]methanone hydrochloride): A novel, potent and selective 5-HT1B receptor antagonist

Claire M. Scott; Christopher J. Langmead; Kirsten Clarke; Paul Adrian Wyman; Paul W. Smith; Kathryn R. Starr; Lee A. Dawson; Gary W. Price; James J. Hagan; Jeannette M. Watson

SB-616234-A possesses high affinity for human 5-HT1B receptors stably expressed in Chinese hamster ovary (CHO) cells (pKi 8.3+/-0.2), and is over 100-fold selective for a range of molecular targets except h5-HT1) receptors (pKi 6.6+/-0.1). Similarly, affinity (pKi) for rat and guinea pig striatal 5-HT1B receptors is 9.2+/-0.1. In [35S]-GTPgammaS binding studies in the human recombinant cell line, SB-616234-A acted as a high affinity antagonist with a pA2 value of 8.6+/-0.2 whilst providing no evidence of agonist activity in this system. In [35S]-GTPgammaS binding studies in rat striatal membranes, SB-616234-A acted as a high affinity antagonist with an apparent pKB of 8.4+/-0.5, again whilst providing no evidence of agonist activity in this system. SB-616234-A (1 microM) potentiated electrically stimulated [3H]-5-HT release from guinea pig and rat cortical slices (S2/S1) ratios of 1.8 and 1.6, respectively). SB-616234-A (0.3-30 mg kg(-1) p.o.) caused a dose-dependent inhibition of ex vivo [3H]-GR125743 binding to rat striatal 5-HT1B receptors with an ED50 of 2.83+/-0.39 mg kg(-1) p.o. Taken together these data suggest that SB-616234-A is a potent and selective 5-HT(1B) autoreceptor antagonist that occupies central 5-HT1B receptors in vivo following oral administration.

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