Publications by authors named "Jeannette M Watson"

33 Publications

Characterisation of a wild-type influenza (A/H1N1) virus strain as an experimental challenge agent in humans.

Virol J 2015 Feb 3;12:13. Epub 2015 Feb 3.

Immune Targeting Systems Ltd, London BioScience Innovation Centre, 2 Royal College Street, London, NW1 0NH, UK.

Background: Human challenge models using respiratory viruses such as influenza are increasingly utilised in the development of novel vaccines and anti-viral modalities and can provide preliminary evidence of protection before evaluation in field trials. We describe the results of a clinical study characterising an A/H1N1 influenza challenge virus in humans.

Methods: The challenge agent, influenza A/California/2009 (H1N1), was manufactured under cGMP conditions and characterised in accordance with regulatory guidelines. A dose-ascending open-label clinical study was conducted in 29 healthy young adults screened sero-negative to the challenge strain. Subjects were intranasally inoculated with three increasing doses of virus and physician-reported signs, subjected-reported symptoms, viral shedding and immunological responses were monitored.

Results: A dose-dependent increase in clinical signs and symptoms was observed with 75% of subjects developing laboratory-confirmed illness at the highest inoculum (3.5 × 10(6) TCID50). At the highest dose, physician or subject-reported signs of infection were classified as mild (all subjects), moderate (50%) and severe (16%) with peak symptoms recorded four days after infection. Clinical signs were correlated with nasal mucus weight (P < .001) and subject-reported symptoms (P < .001). Geometric mean peak viral shedding was log10 5.16 TCID50 and occurred three days after inoculation with a median duration of five days. The safety profile was such that physiological responses to viral infection were mainly restricted to the upper airways but were not of such severity to be of clinical concern.

Conclusions: A highly characterised wild-type Influenza A/California/2009 (H1N1) virus manufactured for clinical use was shown to induce a good infectivity profile in human volunteers. This clinical challenge model can be used for evaluating potential efficacy of vaccines and anti-viral therapeutics.

Trial Registration: NCT02014870.
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http://dx.doi.org/10.1186/s12985-015-0240-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4322439PMC
February 2015

A novel peptide-based pan-influenza A vaccine: a double blind, randomised clinical trial of immunogenicity and safety.

Vaccine 2015 Jan 10;33(2):396-402. Epub 2014 Jun 10.

Immune Targeting Systems Ltd., London, NW1 0NH, UK.

Background: FP-01.1 is a novel synthetic influenza A vaccine consisting of six fluorocarbon-modified 35-mer peptides that encapsulate multiple CD4+ and CD8+ T-cell epitopes and is designed to induce an immune response across a broad population.

Methods: FP-01.1 was evaluated for safety and immunogenicity in a randomised, double-blind, placebo-controlled, dose-escalation, phase I clinical study in healthy adult volunteers (n=49). IFNγ ELISpot assays and multicolour flow cytometry were used to characterise the immune response.

Results: FP-01.1 was safe and well tolerated at all doses tested with a similar adverse event profile in actively vaccinated subjects compared with controls. Maximum immunogenicity was in the 150 μg/peptide dose group where a robust response (243 spots/million PBMC) was demonstrated in 75% subjects compared with 0% in placebo controls. All six peptides were immunogenic. FP-01.1 induced dual CD4+ and CD8+ T cell responses and vaccine-specific T cells cross-recognise divergent influenza strains.

Conclusions: This first-in-human study showed that FP-01.1 has an acceptable safety and tolerability profile and generated robust anti-viral T cell responses in a high proportion of subjects tested. The results support the further clinical testing of FP-01.1 prior to clinical, proof-of-concept, live viral challenge studies.
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http://dx.doi.org/10.1016/j.vaccine.2014.06.006DOI Listing
January 2015

Distinct muscarinic acetylcholine receptor subtypes mediate pre- and postsynaptic effects in rat neocortex.

BMC Neurosci 2012 Apr 27;13:42. Epub 2012 Apr 27.

Center for Anatomy, Institute for Cell Biology and Neurobiology, Charité Universitätsmedizin Berlin, Philippstr 12, 10115 Berlin, Germany.

Background: Cholinergic transmission has been implicated in learning, memory and cognition. However, the cellular effects induced by muscarinic acetylcholine receptors (mAChRs) activation are poorly understood in the neocortex. We investigated the effects of the cholinergic agonist carbachol (CCh) and various agonists and antagonists on neuronal activity in rat neocortical slices using intracellular (sharp microelectrode) and field potential recordings.

Results: CCh increased neuronal firing but reduced synaptic transmission. The increase of neuronal firing was antagonized by pirenzepine (M₁/M₄ mAChRs antagonist) but not by AF-DX 116 (M₂/M₄ mAChRs antagonist). Pirenzepine reversed the depressant effect of CCh on excitatory postsynaptic potential (EPSP) but had marginal effects when applied before CCh. AF-DX 116 antagonized the depression of EPSP when applied before or during CCh. CCh also decreased the paired-pulse inhibition of field potentials and the inhibitory conductances mediated by GABA(A) and GABA(B) receptors. The depression of paired-pulse inhibition was antagonized or prevented by AF-DX 116 or atropine but only marginally by pirenzepine. The inhibitory conductances were unaltered by xanomeline (M₁/M₄ mAChRs agonist), yet the CCh-induced depression was antagonized by AF-DX 116. Linopirdine, a selective M-current blocker, mimicked the effect of CCh on neuronal firing. However, linopirdine had no effect on the amplitude of EPSP or on the paired-pulse inhibition, indicating that M-current is involved in the increase of neuronal excitability but neither in the depression of EPSP nor paired-pulse inhibition.

Conclusions: These data indicate that the three effects are mediated by different mAChRs, the increase in firing being mediated by M₁ mAChR, decrease of inhibition by M₂ mAChR and depression of excitatory transmission by M₄ mAChR. The depression of EPSP and increase of neuronal firing might enhance the signal-to-noise ratio, whereas the concomitant depression of inhibition would facilitate long-term potentiation. Thus, this triade of effects may represent a "neuronal correlate" of attention and learning.
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http://dx.doi.org/10.1186/1471-2202-13-42DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3416661PMC
April 2012

Quantitative analysis reveals multiple mechanisms of allosteric modulation of the mGlu5 receptor in rat astroglia.

Mol Pharmacol 2011 May 14;79(5):874-85. Epub 2011 Feb 14.

Department of Cell Physiology and Pharmacology, University of Leicester, Leicester, United Kingdom.

Positive and negative allosteric modulators (PAMs and NAMs, respectively) of the type 5 metabotropic glutamate (mGlu5) receptor have demonstrable therapeutic potential in an array of neurological and psychiatric disorders. Here, we have used rat cortical astrocytes to investigate how PAMs and NAMs mediate their activity and reveal marked differences between PAMs with respect to their modulation of orthosteric agonist affinity and efficacy. Affinity cooperativity factors (α) were assessed using [(3)H]2-methyl-6-(phenylethynyl)-pyridine (MPEP)-PAM competition binding in the absence and presence of orthosteric agonist, whereas efficacy cooperativity factors (β) were calculated from net affinity/efficacy cooperativity parameters (αβ) obtained from analyses of the abilities of PAMs to potentiate [(3)H]inositol phosphate accumulation in astrocytes stimulated with a submaximal (EC(20)) concentration of orthosteric agonist. We report that whereas 3,3'-difluorobenzaldazine (DFB) and 3-cyano-N-(1,3-diphenyl-1H-prazol-5-yl)benzamide (CDPPB) primarily exert their allosteric modulatory effects through modifying the apparent orthosteric agonist affinity at the astrocyte mGlu5 receptor, the effects of S-(4-fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidinl-1-yl}-methanone (ADX47273) are mediated primarily via efficacy-driven modulation. In [(3)H]MPEP-NAM competition binding assays, both MPEP and 2-(2-(3-methoxyphenyl)ethynyl)-5-methylpyridine (M-5MPEP) defined similar specific binding components, with affinities that were unaltered in the presence of orthosteric agonist, indicating wholly negative efficacy-driven modulations. It is noteworthy that whereas M-5MPEP only partially inhibited orthosteric agonist-stimulated [(3)H]inositol phosphate accumulation in astrocytes, it could completely suppress Ca(2+) oscillations stimulated by quisqualate or (S)-3,5-dihydroxyphenylglycine. In contrast, MPEP was fully inhibitory with respect to both functional responses. The finding that M-5MPEP has different functional effects depending on the endpoint measured is discussed as a possible example of permissive allosteric antagonism.
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http://dx.doi.org/10.1124/mol.110.068882DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3082933PMC
May 2011

The muscarinic M(4) receptor is the functionally predominant subtype in rat and mouse striatum as demonstrated using [(35)S] GTPγS binding.

Eur J Pharmacol 2011 Feb 30;652(1-3):1-6. Epub 2010 Nov 30.

GlaxoSmithKline, New Frontiers Science Park, Harlow, Essex, UK.

We have used selective muscarinic receptor antagonists and M(2) and M(4) receptor knockout (KO) mouse tissue to define the functional muscarinic acetylcholine receptor populations in rodent striatum. [(3)H] NMS binding studies in rat and mouse striatum demonstrated that approximately 30% of muscarinic acetylcholine receptors expressed are M(1) receptors. Radioligand binding studies suggest that the remaining muscarinic acetylcholine receptor population is largely M(4) with small levels of M(2). In agreement, carbachol-induced GTPγS binding studies in M(2) and M(4) receptor KO mouse striatum implicated the M(4) receptor as the predominant functional receptor subtype. Based on these data we have developed a novel, native tissue M(4) receptor [(35)S] GTPγS binding assay. Pharmacological assessment of M(4) receptor agonist and positive 3modulators revealed clear differences in the potencies observed in a human recombinant CHO-M(4) receptor [(35)S] GTPγS binding assay as compared to the native tissue [(35)S] GTPγS binding assay. These differences are believed to reflect differences in receptor reserve between the assay systems as well as differences in compound pharmacology (relative contribution of compound affinity and efficacy to observed potency). These studies have demonstrated the importance of understanding the pharmacology of test compounds in a native environment when predicting in vivo response.
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http://dx.doi.org/10.1016/j.ejphar.2010.10.079DOI Listing
February 2011

The discovery of a series of N-substituted 3-(4-piperidinyl)-1,3-benzoxazolinones and oxindoles as highly brain penetrant, selective muscarinic M1 agonists.

Bioorg Med Chem Lett 2010 Sep 30;20(18):5434-8. Epub 2010 Jul 30.

GlaxoSmithKline, New Frontiers Science Park, 3rd Avenue, Harlow, Essex CM19 5AW, UK.

A series of N-substituted 3-(4-piperidinyl)-1,3-benzoxazolinones and oxindoles are reported which were found to be potent and selective muscarinic M1 agonists. By control of the physicochemical characteristics of the series, particularly the lipophilicity, compounds with good metabolic stability and excellent brain penetration were identified. An exemplar of the series was shown to be pro-cognitive in the novel object recognition rat model of temporal induced memory deficit.
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http://dx.doi.org/10.1016/j.bmcl.2010.07.097DOI Listing
September 2010

Design and synthesis of novel tricyclic benzoxazines as potent 5-HT(1A/B/D) receptor antagonists leading to the discovery of 6-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazine-3-carboxamide (GSK588045).

J Med Chem 2010 Aug;53(15):5827-43

Neurosciences CEDD, GlaxoSmithKline, New Frontiers Science Park, Harlow, Essex, UK.

Bioisoteric replacement of the metabolically labile N-methyl amide group of a series of benzoxazinones with small heterocyclic rings has led to novel series of fused tricyclic benzoxazines which are potent 5-HT(1A/B/D) receptor antagonists with and without concomitant human serotonin transporter (hSerT) activity. Optimizing against multiple parameters in parallel identified 6-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazine-3-carboxamide (GSK588045) as a potent 5-HT(1A/B/D) receptor antagonist with a high degree of selectivity over human ether-a-go-go related gene (hERG) potassium channels, favorable pharmacokinetics, and excellent activity in vivo in rodent pharmacodynamic (PD) models. On the basis of its outstanding overall profile, this compound was progressed as a clinical candidate with the ultimate aim to assess its potential as a faster acting antidepressant/anxiolytic with reduced side-effect burden.
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http://dx.doi.org/10.1021/jm100482nDOI Listing
August 2010

Orthosteric and allosteric modes of interaction of novel selective agonists of the M1 muscarinic acetylcholine receptor.

Mol Pharmacol 2010 Jul 22;78(1):94-104. Epub 2010 Apr 22.

Drug Discovery Biology and, Department of Pharmacology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.

Recent years have witnessed the discovery of novel selective agonists of the M(1) muscarinic acetylcholine (ACh) receptor (mAChR). One mechanism invoked to account for the selectivity of such agents is that they interact with allosteric sites. We investigated the molecular pharmacology of two such agonists, 1-[3-(4-butyl-1-piperidinyl)propyl]-3,4-dihydro-2(1H)-quinolinone (77-LH-28-1) and 4-n-butyl-1-[4-(2-methylphenyl)-4-oxo-1-butyl] piperidine hydrogen chloride (AC-42), at the wild-type M(1) mAChR and three mutant M(1) mAChRs. Both agonists inhibited the binding of the orthosteric antagonist [(3)H]N-methyl scopolamine ([(3)H]NMS) in a manner consistent with orthosteric competition or high negative cooperativity. Functional interaction studies between 77-LH-28-1 and ACh also indicated a competitive mechanism. Dissociation kinetics assays revealed that the agonists could bind allosterically when the orthosteric site was prelabeled with [(3)H]NMS and that 77-LH-28-1 competed with the prototypical allosteric modulator heptane-1,7-bis-[dimethyl-3'-phthalimidopropyl]-ammonium bromide under these conditions. Mutation of the key orthosteric site residues Y(381)A (transmembrane helix 6) and W(101)A (transmembrane helix 3) reduced the affinity of prototypical orthosteric agonists but increased the affinity of the novel agonists. Divergent effects were also noted on agonist signaling efficacies at these mutants. We identified a novel mutation, F(77)I (transmembrane helix 2), which selectively reduced the efficacy of the novel agonists in mediating intracellular Ca(2+) elevation and phosphorylation of extracellular signal regulated kinase 1/2. Molecular modeling suggested a possible "bitopic" binding mode, whereby the agonists extend down into the orthosteric site as well as up toward extracellular receptor regions associated with an allosteric site. It is possible that this bitopic mode may explain the pharmacology of other selective mAChR agonists.
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http://dx.doi.org/10.1124/mol.110.064345DOI Listing
July 2010

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

Recent advances in the discovery of selective and non-selective 5-HT(1D) receptor ligands.

Curr Top Med Chem 2010 ;10(5):479-92

Neuroscience Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex, CM19 5AW, UK.

This article highlights recent advances in the discovery of new agonists, antagonists and partial agonists of the 5-HT(1D) receptor. The field of 5-HT(1D) agonists continues to deliver a number of new potential therapeutic agents, although advances in this field are now more focussed on the clinical evaluation phase. The identification of novel compounds is greater for the 5-HT(1D) receptor antagonists, and whilst few truly selective ligands have been identified, a number of approaches are discussed towards defined mixed-pharmacology profiles. An overview is also given of recent advances in biological and clinical understanding of the receptor.
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http://dx.doi.org/10.2174/156802610791111533DOI Listing
September 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

Effects of positive allosteric modulators on single-cell oscillatory Ca2+ signaling initiated by the type 5 metabotropic glutamate receptor.

Mol Pharmacol 2009 Dec 8;76(6):1302-13. Epub 2009 Sep 8.

Department of Cell Physiology and Pharmacology, University of Leicester, Leicester, UK.

Agonist stimulation of the type 5 metabotropic glutamate (mGlu5) receptor initiates robust oscillatory changes in cytosolic Ca2+ concentration ([Ca2+]i) in single cells by rapid, repeated cycles of phosphorylation/dephosphorylation of the mGlu5 receptor, involving protein kinase C and as-yet-unspecified protein phosphatase activities. An emergent property of this type of Ca2+ oscillation-generating mechanism (termed "dynamic uncoupling") is that once a threshold concentration has been reached to initiate the Ca2+ oscillation, its frequency is largely insensitive to further increases in orthosteric agonist concentration. Here, we report the effects of positive allosteric modulators (PAMs) on the patterns of single-cell Ca2+ signaling in recombinant and native mGlu5 receptor-expressing systems. In a Chinese hamster ovary cell-line (CHO-lac-mGlu5a), none of the mGlu5 receptor PAMs studied [3,3'-difluorobenzaldazine (DFB), N-{4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) methyl]phenyl}-2-hydroxy-benzamide (CPPHA), 3-cyano-N-(1, 3-diphenyl-1H-prazol-5-yl)benzamide (CDPPB), S-(4-fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidinl-1-yl}-methanone (ADX47273)], stimulated a Ca2+ response when applied alone, but each PAM concentration-dependently increased the frequency, without affecting the amplitude, of Ca2+ oscillations induced by glutamate or quisqualate. Therefore, PAMs can cause graded increases (and negative allosteric modulator-graded decreases) in the Ca2+ oscillation frequency stimulated by orthosteric agonist. Initial data in rat cerebrocortical astrocytes demonstrated that similar effects of PAMs could be observed in a native cell background, although at high orthosteric agonist concentrations, PAM addition could much more often be seen to drive rapid Ca2+ oscillations into peak-plateau responses. These data demonstrate that allosteric modulators can "tune" the Ca2+ oscillation frequency initiated by mGlu5 receptor activation, and this might allow pharmacological modification of the downstream processes (e.g., transcriptional regulation) that is unachievable through orthosteric ligand interactions.
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http://dx.doi.org/10.1124/mol.109.059170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2784724PMC
December 2009

Vilazodone: a 5-HT1A receptor agonist/serotonin transporter inhibitor for the treatment of affective disorders.

CNS Neurosci Ther 2009 ;15(2):107-17

Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, Harlow, Essex, UK.

Vilazodone (EMD 68843; 5-{4-[4-(5-cyano-3-indolyl)-butyl]-1-piperazinyl}-benzofuran-2-carboxamide hydrochloride) is a combined serotonin specific reuptake inhibitor (SSRI) and 5-HT1A receptor partial agonist currently under clinical evaluation for the treatment of major depression. This molecule was designed based on the premise that negative feedback circuitry, mediated via 5-HT1 receptors, limits the acute SSRI-induced enhancements in serotonergic neurotransmission. If the hypothesis is correct, combination of SSRI with 5-HT1A partial agonism should temporally enhance the neuroplastic adaptation and subsequently hasten therapeutic efficacy compared to current treatments. Preclinical in vitro evaluation has confirmed vilazodone's primary pharmacological profile both in clonal and native systems, that is, serotonin reuptake blockade and 5-HT1A partial agonism. However, in vivo and in contrast to combination of 8-OH-DPAT and paroxetine, vilazodone selectively enhanced serotonergic output in the prefrontal cortex of rats. Behavioral evaluations, in the ultrasonic vocalization model of anxiety in rats, demonstrated anxiolytic efficacy. In the forced swim test (a putative model of depression), vilazodone also showed efficacy but at a single dose only. In man, vilazodone abolished REM sleep and demonstrated clinical antidepressant efficacy equivalent to an SSRI. Ongoing clinical evaluations will hopefully reveal whether the founding hypothesis was valid and if vilazodone will produce a more rapid onset of antidepressant efficacy.
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http://dx.doi.org/10.1111/j.1755-5949.2008.00067.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6493994PMC
March 2010

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

8-[2-(4-Aryl-1-piperazinyl)ethyl]-2H-1,4-benzoxazin-3(4H)-ones: dual-acting 5-HT1 receptor antagonists and serotonin reuptake inhibitors--part II.

Bioorg Med Chem Lett 2009 Apr 20;19(8):2338-42. Epub 2009 Feb 20.

Neurosciences CEDD, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex, UK.

8-[2-(4-Aryl-1-piperazinyl)ethyl]-2H-1,4-benzoxazin-3(4H)-ones have been identified as highly potent 5-HT(1A/B/D) receptor antagonists with and without additional SerT activity and a high degree of selectivity over hERG potassium channels. Modulation of the different target activities gave compounds with a range of profiles suitable for further in vivo characterization.
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http://dx.doi.org/10.1016/j.bmcl.2009.02.056DOI Listing
April 2009

New quinoline NK3 receptor antagonists with CNS activity.

Bioorg Med Chem Lett 2009 Feb 7;19(3):837-40. Epub 2008 Dec 7.

Medicinal Chemistry, Neuroscience CEDD GlaxoSmithKline Research & Development, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK.

Lead optimisation starting from the previously reported selective quinoline NK(3) receptor antagonists talnetant 2 (SB-223412) and 3 (SB-222200) led to the identification of 3-aminoquinoline NK(3) antagonist 10 (GSK172981) with excellent CNS penetration. Investigation of a structurally related series of sulfonamides with reduced lipophilicity led to the discovery of 20 (GSK256471). Both 10 and 20 are high affinity, potent NK(3) receptor antagonists which despite having different degrees of CNS penetration produced excellent NK(3) receptor occupancy in an ex vivo binding study in gerbil cortex.
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http://dx.doi.org/10.1016/j.bmcl.2008.12.005DOI Listing
February 2009

Novel 5-HT(1A/1B/1D) receptors antagonists with potent 5-HT reuptake inhibitory activity.

Bioorg Med Chem Lett 2008 Oct 3;18(20):5581-5. Epub 2008 Sep 3.

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

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.
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http://dx.doi.org/10.1016/j.bmcl.2008.08.110DOI Listing
October 2008

6-[2-(4-Aryl-1-piperazinyl)ethyl]-2H-1,4-benzoxazin-3(4H)-ones: dual-acting 5-HT1 receptor antagonists and serotonin reuptake inhibitors.

Bioorg Med Chem Lett 2008 Oct 28;18(20):5653-6. Epub 2008 Aug 28.

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

Investigation of a series 6-[2-(4-aryl-1-piperazinyl)ethyl]-2H-1,4-benzoxazin-3(4H)-ones has led to the discovery of potent 5-HT(1A/1B/1D) receptor antagonists with and without additional SerT affinity. Modulation of the different target activities gave compounds with a range of profiles suitable for further in vivo characterization.
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http://dx.doi.org/10.1016/j.bmcl.2008.08.084DOI Listing
October 2008

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

J Med Chem 2008 May 24;51(10):2887-90. Epub 2008 Apr 24.

Psychiatry Centre of Excellence for Drug Discovery and Molecular Discovery Research, GlaxoSmithKline, Essex, UK.

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.
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http://dx.doi.org/10.1021/jm8001444DOI Listing
May 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

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

Neuropsychopharmacology 2008 Jun 29;33(7):1642-52. Epub 2007 Aug 29.

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

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.
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http://dx.doi.org/10.1038/sj.npp.1301549DOI Listing
June 2008

Studies on a series of potent, orally bioavailable, 5-HT(1) receptor ligands.

Bioorg Med Chem Lett 2007 Sep 30;17(18):5214-7. Epub 2007 Jun 30.

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

A series of 5-(piperidinylethyloxy)quinoline 5-HT(1) receptor ligands have been studied by elaboration of the series of dual 5-HT(1)-SSRIs reported previously. These new compounds display a different pharmacological profile with potent affinity across the 5-HT(1A), 5-HT(1B) and 5-HT(1D) receptors and selectivity against the serotonin transporter. Furthermore, they have improved pharmacokinetic profiles and CNS penetration.
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http://dx.doi.org/10.1016/j.bmcl.2007.06.078DOI Listing
September 2007

Characterization of the potent 5-HT(1A/B) receptor antagonist and serotonin reuptake inhibitor SB-649915: preclinical evidence for hastened onset of antidepressant/anxiolytic efficacy.

CNS Drug Rev 2007 ;13(2):206-23

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

An increase in brain serotonin (5-HT) levels is thought to be a key mechanism of action responsible for generating antidepressant efficacy. It has been proven that selective serotonin reuptake inhibitors are effective antidepressants, but the delay to therapeutic onset of these agents is thought to be due to the time required for 5-HT1A, and possibly 5-HT1B, autoreceptors to desensitize. Therefore, an agent incorporating 5-HT reuptake inhibition coupled with 5-HT1A and/or 5-HT1B autoreceptor antagonism may provide a fast-acting clinical agent. The current studies review the profile of SB-649915 (6-[(1-{2-[(2-methylquinolin-5-yl)oxy]ethyl}piperidin-4-yl)methyl]-2H-1,4-benzoxazin-3(4H)-one), a novel compound with high affinity for human (h) 5-HT1A and 5-HT1B receptors (pKi values of 8.6 and 8.0, respectively) as well as the (h) 5-HT transporter (SERT) (pKi value of 9.3). SB-649915 behaved as an antagonist at both 5-HT1A and 5-HT1B receptors in vitro and in vivo, reversing 5-HT, (+)8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) and SKF99101-induced functional/behavioral responses. Furthermore, it inhibited [3H]5-HT reuptake in rat cortical synaptosomes, in vitro and ex vivo. In electrophysiological studies SB-649915 had no effect on rat dorsal raphe neuronal cell firing per se, but reversed 8-OH-DPAT-induced inhibition of firing both in vitro and in vivo. In addition, in a microdialysis study, it produced an acute increase in extracellular 5-HT in forebrain structures of the rat. Finally, SB-649915 demonstrated acute anxiolytic activity in both rodent and non-human primate and reduced the latency to onset of anxiolytic behavior, compared to paroxetine, in the rat social interaction paradigm. In summary, SB-649915 is a novel, potent 5-HT1A/1B autoreceptor antagonist, and 5-HT reuptake inhibitor. This particular pharmacological profile provides a novel mechanism that could offer fast-acting antidepressant activity.
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http://dx.doi.org/10.1111/j.1527-3458.2007.00012.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6726354PMC
September 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

3,4-Dihydro-2H-benzoxazinones as dual-acting 5-HT1A receptor antagonists and serotonin reuptake inhibitors.

Bioorg Med Chem Lett 2007 Feb 15;17(4):1033-6. Epub 2006 Nov 15.

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

Investigation of halogen substitution in lead compound 1 has led to the identification of analogues which combine high affinity for 5-HT(1A) receptors and potent serotonin reuptake inhibitory activity. Several compounds show an improved selectivity over 5-HT(1B) and 5-HT(1D) receptors and a superior pharmacokinetic profile in the rat.
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http://dx.doi.org/10.1016/j.bmcl.2006.11.031DOI Listing
February 2007

8-Piperazinyl-2,3-dihydropyrrolo[3,2-g]isoquinolines: potent, selective, orally bioavailable 5-HT1 receptor ligands.

Bioorg Med Chem Lett 2005 Oct;15(19):4370-4

High Throughput Chemistry, Discovery Research, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow Essex CM19 5AW, UK.

The novel 8-piperazinyl-2,3-dihydropyrroloisoquinoline template was synthesized in nine steps. The template was N-substituted to give a series of compounds showing binding to human cloned 5-HT1A, 5-HT1B and 5-HT1D receptors with pKi's greater than 9 and selectivities up to 1000-fold against other serotonin, dopamine and adrenergic receptors. Several compounds were shown to possess weak partial agonist activity in cloned receptors, which translated to antagonism in in vitro studies.
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http://dx.doi.org/10.1016/j.bmcl.2005.06.042DOI Listing
October 2005

Discovery of the first potent, selective 5-hydroxytryptamine1D receptor antagonist.

J Med Chem 2005 May;48(10):3478-80

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

A series of 5-(piperidinylethyloxy)quinoline 5-hydroxytryptamine(1D) (5-HT(1D)) receptor antagonists have been discovered from elaboration of the series of dual 5-hydroxytryptamine(1)-selective serotonin reuptake inhibitors (5HT(1)-SSRIs) reported previously. This is the first report of highly potent, selective antagonists for the 5-HT(1D) receptor, which represents an extremely useful set of pharmacological tools for further understanding the roles of the 5-HT(1) receptor subtypes.
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http://dx.doi.org/10.1021/jm049039vDOI Listing
May 2005

3,4-Dihydro-2H-benzoxazinones are 5-HT(1A) receptor antagonists with potent 5-HT reuptake inhibitory activity.

Bioorg Med Chem Lett 2005 Feb;15(3):737-41

Psychiatry Center of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK.

Starting from a high throughput screening hit, a series of 3,4-dihydro-2H-benzoxazinones has been identified with both high affinity for the 5-HT(1A) receptor and potent 5-HT reuptake inhibitory activity. The 5-(2-methyl)quinolinyloxy derivative combined high 5-HT(1A/1B/1D) receptor affinities with low intrinsic activity and potent inhibition of the 5-HT reuptake site (pK(i)8.2). This compound also had good oral bioavailability and brain penetration in the rat.
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http://dx.doi.org/10.1016/j.bmcl.2004.11.030DOI Listing
February 2005

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