Dr Andrew Thompson University positionSenior Research Associate DepartmentsHome pagehttp://ajt44.altervista.org/ (personal home page) Research ThemeInterestsI am an experienced neuroscientist / pharmacologist with exposure to a broad range of techniques. This has included the development of a simple and information-rich fluorometric microplate assay for simultaneously identifying novel agonists, antagonists and allosteric modulators using a fragment-based drug discovery (FBDD) approach. I support this drug-discovery with patch-clamp / TEVC electrophysiology, flow cytometry, fluorescence microscopy and radioligand binding on hit compounds. I determine detailed kinetic parameters for novel compounds and interpret their binding modes using in silico modelling and docking. The models are validated using receptor mutagenesis and compound structure-activity relationships (SAR). I find this work interesting and am keen to pursue these types of drug discovery projects.  Identification of novel P2X1 ligands as therapeutic candidates for preventing thrombosis. View image full-size (5000x3296 pixels) Research Focus
EquipmentCalcium imaging Cell culture Cell culture & animal handling: primary cells & cell lines Computational modelling Confocal microscopy Electrophysiological recording techniques Fluorescence microscopy Fluorescent microplate assays (e.g. FlexStation) Fragment-based drug-discovery (FBDD) Immunocytochemistry Immunohistochemistry In silico modelling & docking Intracellular recording Ligand SAR Ligand-gated & Voltage-gated ion channels Manual & automated patch-clamp Manual & automated two-electrode voltage-clamp (TEVC) Microscopy Microscopy: TIRF, Confocal, SEM & TEM Molecular biology Protein purification Radioligand saturation/competition & kinetics Recombinant protein expression Voltage-clamp fluorometry Whole cell patch clamp Collaborators
Associated News ItemsPublications2015Lochner M, Thompson AJ (2015), “A review of fluorescent ligands for studying 5-HT3 receptors.” Neuropharmacology Details 2014Jack T, Ruepp M-D, Thompson AJ, Muhlemann O, Lochner M (2014), “Synthesis and characterisation of photoaffinity probes that target the 5-HT3 receptor. ” Chimia 68; 239-242 Jack T, Simonin J, Ruepp MD, Thompson AJ, Gertsch J, Lochner M (2014), “Characterizing New Fluorescent Tools for Studying 5-HT3 Receptor Pharmacology.” Neuropharmacology Details Lochner M, Thompson AJ (2014), “The Antimalarial Drug Proguanil Is an Antagonist at 5-HT3 Receptors.” J Pharmacol Exp Ther 351(3):674-84 Details Thompson AJ, Alqazzaz M, Price KL, Weston DA, Lummis SC (2014), “Phenylalanine in the pore of the Erwinia ligand-gated ion channel modulates picrotoxinin potency but not receptor function.” Biochemistry 53(39):6183-8 Details Thompson AJ, Verheij MH, Verbeek J, Windhorst AD, de Esch IJ, Lummis SC (2014), “The binding characteristics and orientation of a novel radioligand with distinct properties at 5-HT3A and 5-HT3AB receptors.” Neuropharmacology 86:378-88 Details Ulens C, Spurny R, Thompson AJ, Alqazzaz M, Debaveye S, Han L, Price K, Villalgordo JM, Tresadern G, Lynch JW, Lummis SC (2014), “The prokaryote ligand-gated ion channel ELIC captured in a pore blocker-bound conformation by the Alzheimer's disease drug memantine.” Structure 22(10):1399-407 Details 2013Del Cadia M, De Rienzo F, Weston DA, Thompson AJ, Menziani MC, Lummis SC (2013), “Exploring a potential palonosetron allosteric binding site in the 5-HT3 receptor.” Bioorg Med Chem 21(23):7523-8 Details Jarvis GE, Thompson AJ (2013), “A golden approach to ion channel inhibition.” Trends Pharmacol Sci 34(9):481-8 Details Kesters D, Thompson AJ, Brams M, van Elk R, Spurny R, Geitmann M, Villalgordo JM, Guskov A, Danielson UH, Lummis SC, Smit AB, Ulens C (2013), “Structural basis of ligand recognition in 5-HT3 receptors.” EMBO Rep 14(1):49-56 Details Lummis SC, Thompson AJ (2013), “Agonists and antagonists induce different palonosetron dissociation rates in 5-HT3A and 5-HT3AB receptors.” Neuropharmacology Details Thompson AJ (2013), “Recent developments in 5-HT3 receptor pharmacology.” Trends Pharmacol Sci 34(2):100-9 Details Thompson AJ, Lummis SC (2013), “Discriminating between 5-HT3 A and 5-HT3 AB receptors.” Br J Pharmacol Details Thompson AJ, Lummis SC (2013), “A single channel mutation alters agonist efficacy at 5-HT3 A and 5-HT3 AB receptors.” Br J Pharmacol 170(2):391-402 Details Thompson AJ, Verheij MH, van Muijlwijk-Koezen JE, Lummis SC, Leurs R, de Esch IJ (2013), “Structure-activity relationships of quinoxaline-based 5-HT3A and 5-HT3AB receptor-selective ligands.” ChemMedChem 8(6):946-55 Details 2012Akdemir A, Edink E, Thompson AJ, Lummis SC, Kooistra AJ, de Graaf C, de Esch IJ (2012), “Identification of novel α7 nicotinic receptor ligands by in silico screening against the crystal structure of a chimeric α7 receptor ligand binding domain.” Bioorg Med Chem 20(19):5992-6002 Details Huang SH, Lewis TM, Lummis SC, Thompson AJ, Chebib M, Johnston GA, Duke RK (2012), “Mixed antagonistic effects of the ginkgolides at recombinant human ρ1 GABAC receptors.” Neuropharmacology 63(6):1127-39 Details Simonin J, Vernekar SK, Thompson AJ, Hothersall JD, Connolly CN, Lummis SC, Lochner M (2012), “High-affinity fluorescent ligands for the 5-HT(3) receptor.” Bioorg Med Chem Lett 22(2):1151-5 Details Thompson AJ, Alqazzaz M, Ulens C, Lummis SC (2012), “The pharmacological profile of ELIC, a prokaryotic GABA-gated receptor.” Neuropharmacology 63(4):761-7 Details Thompson AJ, McGonigle I, Duke R, Johnston GA, Lummis SC (2012), “A single amino acid determines the toxicity of Ginkgo biloba extracts.” FASEB J 26(5):1884-91 Details Thompson AJ, Verheij MH, de Esch IJ, Lummis SC (2012), “VUF10166, a novel compound with differing activities at 5-HT₃A and 5-HT₃AB receptors.” J Pharmacol Exp Ther 341(2):350-9 Details Utkin YN, Weise C, Kasheverov IE, Andreeva TV, Kryukova EV, Zhmak MN, Starkov VG, Hoang NA, Bertrand D, Ramerstorfer J, Sieghart W, Thompson AJ, Lummis SC, Tsetlin VI (2012), “Azemiopsin from Azemiops feae viper venom, a novel polypeptide ligand of nicotinic acetylcholine receptor.” J Biol Chem 287(32):27079-86 Details Verheij MH, Thompson AJ, van Muijlwijk-Koezen JE, Lummis SC, Leurs R, de Esch IJ (2012), “Design, Synthesis, and Structure-Activity Relationships of Highly Potent 5-HT(3) Receptor Ligands.” J Med Chem Details 2011Alqazzaz M, Thompson AJ, Price KL, Breitinger HG, Lummis SC (2011), “Cys-loop receptor channel blockers also block GLIC.” Biophys J 101(12):2912-8 Details Lummis SCR, Thompson AJ, Bencherif M, Lester HA (2011), “Varenicline is a Potent Agonist of the Human 5-HT3 Receptor.” JPET 339; 125-131 Thompson AJ, Duke RK, Lummis SC (2011), “Binding sites for bilobalide, diltiazem, ginkgolide, and picrotoxinin at the 5-HT3 receptor.” Mol Pharmacol 80(1):183-90 Details Thompson AJ, Jarvis GE, Duke RK, Johnston GA, Lummis SC (2011), “Ginkgolide B and bilobalide block the pore of the 5-HT(3) receptor at a location that overlaps the picrotoxin binding site.” Neuropharmacology 60(2-3):488-95 Details Thompson AJ, Price KL, Lummis SC (2011), “Cysteine modification reveals which subunits form the ligand binding site in human heteromeric 5-HT3AB receptors.” J Physiol 589(Pt 17):4243-57 Details Verheij MH, de Graaf C, de Kloe GE, Nijmeijer S, Vischer HF, Smits RA, Zuiderveld OP, Hulscher S, Silvestri L, Thompson AJ, van Muijlwijk-Koezen JE, Lummis SC, Leurs R, de Esch IJ (2011), “Fragment library screening reveals remarkable similarities between the G protein-coupled receptor histamine H₄ and the ion channel serotonin 5-HT₃A.” Bioorg Med Chem Lett 21(18):5460-4 Details Wheeler DW, Thompson AJ, Corletto F, Reckless J, Loke JC, Lapaque N, Grant AJ, Mastroeni P, Grainger DJ, Padgett CL, O'Brien JA, Miller NG, Trowsdale J, Lummis SC, Menon DK, Beech JS (2011), “Anaesthetic impairment of immune function is mediated via GABA(A) receptors.” PLoS One 6(2):e17152 Details 2010Quek GXJ, Lin D, Halliday JI, Absalom N, Ambrus JI, Thompson AJ, Lochner M, Lummis SCR, McLeod MD, Chebib M (2010), “ Identifying the Binding Site of Novel Methyllycaconitine (MLA) Analogs at alpha4beta2 Nicotinic Acetylcholine Receptors.” ACS Chem Neurosci 1: 796-809 Thompson AJ, Lester HA, Lummis SC (2010), “The structural basis of function in Cys-loop receptors.” Q Rev Biophys 43(4):449-99 Details Thompson AJ, Verheij MH, Leurs R, De Esch IJ, Lummis SC (2010), “An efficient and information-rich biochemical method design for fragment library screening on ion channels.” Biotechniques 49(5):822-9 Details Vernekar SK, Hallaq HY, Clarkson G, Thompson AJ, Silvestri L, Lummis SC, Lochner M (2010), “Toward biophysical probes for the 5-HT3 receptor: structure-activity relationship study of granisetron derivatives.” J Med Chem 53(5):2324-8 Details 2009Thompson AJ, Lummis SC (2009), “Calcium modulation of 5-HT3 receptor binding and function.” Neuropharmacology 56(1):285-91 Details Thompson AJ, Mander PK, Brown GC (2009), “The NO donor DETA-NONOate reversibly activates an inward current in neurones and is not mediated by the released nitric oxide.” Br J Pharmacol 158(5):1338-43 Details 2008Price KL, Bower KS, Thompson AJ, Lester HA, Dougherty DA, Lummis SC (2008), “A hydrogen bond in loop A is critical for the binding and function of the 5-HT3 receptor.” Biochemistry 47(24):6370-7 Details Thompson AJ, Lochner M, Lummis SC (2008), “Loop B is a major structural component of the 5-HT3 receptor.” Biophys J 95(12):5728-36 Details Thompson AJ, Lummis SC (2008), “Antimalarial drugs inhibit human 5-HT(3) and GABA(A) but not GABA(C) receptors.” Br J Pharmacol 153(8):1686-96 Details 2007Thompson AJ, Lochner M, Lummis SC (2007), “The antimalarial drugs quinine, chloroquine and mefloquine are antagonists at 5-HT3 receptors.” Br J Pharmacol 151(5):666-77 Details Thompson AJ, Lummis SC (2007), “The 5-HT3 receptor as a therapeutic target.” Expert Opin Ther Targets 11(4):527-40 Details 2006Sullivan NL, Thompson AJ, Price KL, Lummis SC (2006), “Defining the roles of Asn-128, Glu-129 and Phe-130 in loop A of the 5-HT3 receptor.” Mol Membr Biol 23(5):442-51 Details Thompson AJ, Chau PL, Chan SL, Lummis SC (2006), “Unbinding pathways of an agonist and an antagonist from the 5-HT3 receptor.” Biophys J 90(6):1979-91 Details Thompson AJ, Lummis SC (2006), “5-HT3 receptors.” Curr Pharm Des 12(28):3615-30 Details Thompson AJ, Lummis SCR (2006), “The Relationship Between Structure and Function in the 5-HT3 Receptor: The Transmembrane Domain. In, Biological and Biophysical Aspects of Ligand-Gated Ion Channel Receptor Superfamilies.” Ed. Arias, H. R. Research Signpost, Kerala, India 155-170 Thompson AJ, Padgett CL, Lummis SC (2006), “Mutagenesis and molecular modeling reveal the importance of the 5-HT3 receptor F-loop.” J Biol Chem 281(24):16576-82 Details Thompson AJ, Sullivan NL, Lummis SC (2006), “Characterization of 5-HT3 receptor mutations identified in schizophrenic patients.” J Mol Neurosci 30(3):273-81 Details Thompson AJ, Zhang L, Lummis SCR (2006), “The 5-HT3 Receptor.” The serotonin receptors: from molecular pharmacology to human therapeutics. 439-457 2005Thompson AJ, Price KL, Reeves DC, Chan SL, Chau PL, Lummis SC (2005), “Locating an antagonist in the 5-HT3 receptor binding site using modeling and radioligand binding.” J Biol Chem 280(21):20476-82 Details 2003Thompson AJ, Lummis SC (2003), “A single ring of charged amino acids at one end of the pore can control ion selectivity in the 5-HT3 receptor.” Br J Pharmacol 140(2):359-65 Details 2000Hubbard PC, Thompson AJ, Lummis SC (2000), “Functional differences between splice variants of the murine 5-HT(3A) receptor: possible role for phosphorylation.” Brain Res Mol Brain Res 81(1-2):101-8 Details 1999Duce IR, Khan TR, Green AC, Thompson AJ, Warburton SPM, Wong JT (1999), “Calcium Channels in Insects.” Progress in Neuropharmacology and Neurotoxicology of Pesticides and Drugs. Ed Beadle D. J, Royal Soc. Chem. Cambridge: 56-66 1998Schuler TH, Martinez-Torres D, Thompson AJ, Denholm I, Devonshire AL, Duce IR, Williamson MS (1998), “Toxicological, Electrophysiological, and Molecular Characterisation of Knockdown Resistance to Pyrethroid Insecticides in the Diamondback Moth, Plutella xylostella (L.). ” Pest. Biochem. Physiol. 59: 169-182 1996Schuler TH, Martinez-Torres D, Thompson AJ, Denholm I, Devonshire AL, Duce IR, Williamson MS (1996), “Characterisation of knockdown resistance to pyrethroid insecticides in Plutella xylostella.” The Management of Diamondback Moth and Other Crucifer Pests. Proc. 3rd Int. Workshop, Kuala Lumpur, Malaysia, 29 Oct.-1 Nov., 1996 (Eds Sivapragasam A, Loke WH, Hussan AK, Lim, GS. 215-218 |
