Genomes and Genes
A J Brown
Affiliation: GlaxoSmithKline Research and Development
- The Orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acidsAndrew J Brown
Department of 7TMR Systems Research, GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom
J Biol Chem 278:11312-9. 2003..The identity of the cognate physiological ligands for these receptors is not clear, although propionate is known to occur in vivo at high concentrations under certain pathophysiological conditions...
- A family of fatty acid binding receptorsAndrew J Brown
Department of 7TMR Assay Development and Compound Profiling ADCP, GlaxoSmithKline, New Frontiers Science Park, Harlow, Essex, UK
DNA Cell Biol 24:54-61. 2005..Here we summarize the identification, structure, and pharmacology of the receptors and speculate on the respective physiological roles that the GPR40 family members may play...
- Pharmacology of GPR55 in yeast and identification of GSK494581A as a mixed-activity glycine transporter subtype 1 inhibitor and GPR55 agonistAndrew J Brown
Screening and Compound Profiling, Medicines Research Centre, GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK
J Pharmacol Exp Ther 337:236-46. 2011....
- Novel cannabinoid receptorsA J Brown
Department of Screening and Compound Profiling, Molecular Discovery Research, GlaxoSmithKline, Essex, UK
Br J Pharmacol 152:567-75. 2007....
- Mapping of a yeast G protein betagamma signaling interactionS J Dowell
Glaxo Wellcome Research and Development, Stevenage, SG1 2NY, United Kingdom
Genetics 150:1407-17. 1998..Identification of the Gbetagamma coiled-coil in Ste5p binding may set a precedent for Gbetagamma-effector interactions in more complex organisms...
- The novel endocannabinoid receptor GPR55 is activated by atypical cannabinoids but does not mediate their vasodilator effectsD G Johns
GlaxoSmithKline, Cardiovascular and Urogenital Center for Excellence in Drug Discovery, Vascular Biology and Thrombosis, King of Prussia, PA 19406, USA
Br J Pharmacol 152:825-31. 2007..The purpose of the present study was to test the hypothesis that human recombinant GPR55 is activated by atypical cannabinoids and mediates vasodilator responses to these agents...
- The G-protein-coupled receptor 40 family (GPR40-GPR43) and its role in nutrient sensingD K Covington
Department of Molecular Pharmacology, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709, USA
Biochem Soc Trans 34:770-3. 2006..These common themes implicate GPR40, GPR41 and GPR43 in playing significant roles in metabolic diseases, such as diabetes, obesity and the metabolic syndrome...
- Synthesis and evaluation of 3-amino-6-aryl-pyridazines as selective CB(2) agonists for the treatment of inflammatory painRobert J Gleave
Pain and Neuroexcitability Discovery Performance Unit, Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Cold Harbour Lane, Harlow, Essex CM19 5AW, United Kingdom
Bioorg Med Chem Lett 20:465-8. 2010..Details of the investigation of structure-activity relationships (SAR) are disclosed, which led to the identification of pyridazine analogue 35, a compound with high potency in an in vivo model of inflammatory pain...
- 2-Amino-5-aryl-pyridines as selective CB2 agonists: synthesis and investigation of structure-activity relationshipsRobert J Gleave
Pain and Neuroexcitability Discovery Performance Unit, Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Harlow, Essex CM19 5AW, United Kingdom
Bioorg Med Chem Lett 19:6578-81. 2009..Described herein are the results of an investigation of the structure-activity relationships (SAR) which led to the identification a number of potent and selective agonists...
- Discovery of 1-[4-(3-chlorophenylamino)-1-methyl-1H-pyrrolo[3,2-c]pyridin-7-yl]-1-morpholin-4-ylmethanone (GSK554418A), a brain penetrant 5-azaindole CB2 agonist for the treatment of chronic painGerard M P Giblin
Neurosciences CEDD, GlaxoSmithKline, New Frontiers Science Park, Harlow, Essex, UK
J Med Chem 52:5785-8. 2009..The template was redesigned, and the resulting 5-azaindole 36 was a potent CB(2) agonist with high CNS penetration. This compound was efficacious in the acute model and the chronic joint pain model...
- Pyridine-3-carboxamides as novel CB(2) agonists for analgesiaWilliam L Mitchell
GlaxoSmithKline plc, Neurosciences Centre of Excellence for Drug Discovery, New Frontiers Science Park, Third Avenue, Harlow, Essex, UK
Bioorg Med Chem Lett 19:259-63. 2009..The SAR of this new template was evaluated and culminated in the identification of analogue 14a which demonstrated efficacy in an in vivo model of inflammatory pain...
- The putative cannabinoid receptor GPR55 plays a role in mechanical hyperalgesia associated with inflammatory and neuropathic painPenny C Staton
Neurology Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK
Pain 139:225-36. 2008..These data clearly suggest that the manipulation of GPR55 may have therapeutic potential in the treatment of both inflammatory and neuropathic pain...
- Molecular identification of high and low affinity receptors for nicotinic acidAlan Wise
Department of 7TMR Systems Research, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, United Kingdom
J Biol Chem 278:9869-74. 2003..The discovery of HM74A as a molecular target for nicotinic acid may facilitate the discovery of superior drug molecules to treat dyslipidemia...
- Discovery of 2-[(2,4-dichlorophenyl)amino]-N-[(tetrahydro- 2H-pyran-4-yl)methyl]-4-(trifluoromethyl)- 5-pyrimidinecarboxamide, a selective CB2 receptor agonist for the treatment of inflammatory painGerard M P Giblin
Neurology and GI Centre of Excellence for Drug Discovery, Molecular Discovery Research, GlaxoSmithKline, New Frontiers Park, Harlow, Essex, CM19 5AW, UK
J Med Chem 50:2597-600. 2007..Subsequent lead optimization identified 35, GW842166X, as the optimal compound in the series. 35 has an oral ED50 of 0.1 mg/kg in the rat FCA model of inflammatory pain and was selected as a clinical candidate for this indication...
- Mating in mushrooms: increasing the chances but prolonging the affairA J Brown
Molecular Pharmacology, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, SG1 2NY, Stevenage, UK
Trends Genet 17:393-400. 2001..The mating-type genes, which encode pheromones, pheromone receptors and homeodomain transcription factors, have crucial roles in regulating the complex developmental programme by which the dikaryon is formed...
- Is GPR55 an anandamide receptor?Andrew J Brown
Department of Screening and Compound Profiling, Molecular Discovery Research, GlaxoSmithKline, New Frontiers Science Park, GlaxoSmithKline, Essex, UK
Vitam Horm 81:111-37. 2009..Overall, it appears that GPR55 has several signaling modalities and that, while anandamide can activate systems containing this receptor, GPR55 cannot yet be primarily designated a receptor for this endocannabinoid...
- Yeast assays for G-protein-coupled receptorsS J Dowell
GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK
Receptors Channels 8:343-52. 2002..Yeast genetics has also been applied to a functional analysis of GPCRs and peptide ligands. In this review we describe the historical development of yeast GPCR assay systems and their current applications...
- Yeast assays for G protein-coupled receptorsSimon J Dowell
Department of Biological Reagent and Assay Development, GlaxoSmithKline, Hertfordshire, UK
Methods Mol Biol 552:213-29. 2009..A number of parameters may be optimized to generate robust experimental formats, in high-density microtiter plates, that may be used for ligand identification and pharmacological characterization...
- The origin of multiple B mating specificities in Coprinus cinereusMeritxell Riquelme
Department of Plant Sciences, University of Oxford, Oxford OX1 3RB, United Kingdom
Genetics 170:1105-19. 2005..While additional allelic versions may occur in nature, the number of B specificities possible by combination of the alleles that we describe is 70, close to previous estimates based on population analysis...
- Uncovering the pharmacology of the G protein-coupled receptor GPR40: high apparent constitutive activity in guanosine 5'-O-(3-[35S]thio)triphosphate binding studies reflects binding of an endogenous agonistLeigh A Stoddart
Davidson Building University of Glasgow, Glasgow G12 8QQ, Scotland, UK
Mol Pharmacol 71:994-1005. 2007....
- Effects of 25-hydroxycholesterol on cholesterol esterification and sterol regulatory element-binding protein processing are dissociable: implications for cholesterol movement to the regulatory pool in the endoplasmic reticulumXiming Du
School of Biotechnology and Biomolecular Sciences, Biological Sciences Building D26, University of New South Wales, Sydney, 2052, Australia
J Biol Chem 279:47010-6. 2004..In light of our results, we question the security of previous work that has inferred cholesterol transport to the ER regulatory pool based solely on cholesterol esterification...
- Rapamycin down-regulates LDL-receptor expression independently of SREBP-2Laura J Sharpe
BABS, School of Biotechnology and Biomolecular Sciences, Biosciences Building D26, University of New South Wales, Sydney, NSW 2052, Australia
Biochem Biophys Res Commun 373:670-4. 2008..Rapamycin did not affect mRNA stability, so the decrease in LDL-receptor gene expression is likely to be occurring at the transcriptional level, although independently of SREBP-2...
- ABCA1 and ABCG1 synergize to mediate cholesterol export to apoA-IIngrid C Gelissen
Centre for Vascular Research, School of Medical Sciences, University of New South Wales, Kensington, Australia
Arterioscler Thromb Vasc Biol 26:534-40. 2006..To study the acceptor specificity for human ABCG1 (hABCG1)-mediated cholesterol efflux...
- Fld1p, a functional homologue of human seipin, regulates the size of lipid droplets in yeastWeihua Fei
Department of Biochemistry, National University of Singapore, Singapore 117597, Republic of Singapore
J Cell Biol 180:473-82. 2008..These results suggest that an evolutionally conserved function of seipin in phospholipid metabolism and LD formation may be functionally important in human adipogenesis...
- Endogenous 24(S),25-epoxycholesterol fine-tunes acute control of cellular cholesterol homeostasisJenny Wong
School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney 2052, Australia
J Biol Chem 283:700-7. 2008..Therefore, in the absence of 24,25EC, fine-tuning of the acute regulation of cholesterol homeostasis is lost, supporting the hypothesis that 24,25EC functions to protect the cell against the accumulation of newly synthesized cholesterol...
- Involvement of Akt in ER-to-Golgi transport of SCAP/SREBP: a link between a key cell proliferative pathway and membrane synthesisXiming Du
School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney 2052, Australia
Mol Biol Cell 17:2735-45. 2006..Our results provide a crucial mechanistic link between the SREBP and PI3K/Akt pathways that may be reconciled teleologically because synthesis of new membrane is an absolute requirement for cell growth and proliferation...
- G protein-coupled receptors for free fatty acidsGraeme Milligan
Molecular Pharmacology Group, Division of Biochemistry and Molecular Biology, Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow G12 8QQ, Scotland, UK
Cell Signal 18:1360-5. 2006....
- Cholesterol addition to ER membranes alters conformation of SCAP, the SREBP escort protein that regulates cholesterol metabolismAndrew J Brown
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Mol Cell 10:237-45. 2002..These studies demonstrate an in vitro effect of cholesterol on the sterol regulatory machinery...
- Synthesis of the oxysterol, 24(S), 25-epoxycholesterol, parallels cholesterol production and may protect against cellular accumulation of newly-synthesized cholesterolJenny Wong
School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney, Australia
Lipids Health Dis 6:10. 2007..This leads to the intriguing paradox: why inhibit production of an apparently important regulator of cholesterol homeostasis when it is needed most?..