Trine Kvist

July 2008 – present: PhD student, Dept. of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen (Financed by Programme of Excellence on Ionotropic Glutamate Receptors GluTarget)).

January – March 2011: Research assistant, Dept. of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen.

February – June 2008: Research assistant, Dept. of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen.

February 2007 – February 2008: Scholar stipendiat, Dept. of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen (Financed by the Drug Research Academy).

September 2002 – March 2008: M.Sc. (Pharm), Faculty of Pharmaceutical Sciences, University of Copenhagen.

March – October 2009 + March – April 2010: Visiting graduate student in the laboratory of Prof. Stephen F. Traynelis, Dept. of Pharmacology, Emory University School of Medicine, Atlanta, USA

August – December 2006: Visiting graduate student in the laboratory of Assistant Professor Jennifer Laurence, Dept. of Pharmaceutical Chemistry, University of Kansas, Kansas, USA.

2009:
The Minister of Science, Technology and Innovation’s EliteForsk travel prize

2007:
The Drug Research Academy Scholarship

2006:
Denmark-America Foundation

Novel pharmacological modulators of NMDA receptors

Background
7 different NMDA subunits (NR1, NR2A-D, NR3A-B) have been cloned that form functional excitatory NMDA receptors by co-assembly of two NR1 subunits with either two NR2 or NR3 subunits. The NR1/NR2 receptors are activated by the simultaneous binding of glycine and glutamate to the NR1 and NR2 subunits, respectively, whereas NR1/NR3 receptors are activated by binding of glycine.

NMDA receptors play pivotal roles in fast glutamatergic neurotransmission and are critically involved in many important neuronal functions including frequency encoding of information, synaptic plasticity, and neuronal development. Under a variety of acute conditions such as ischemia, seizures or traumatic brain injury, the release of excess amounts of glutamate and the resultant NMDA receptor-mediated Ca²⁺ flux into the cell may be of sufficient magnitude as to promote neuronal death, i.e. the phenomenon termed “excitotoxicity”. Under chronic conditions of enhanced neuronal susceptibility, as in Parkinson’s, Huntington’s, and Alzheimer’s diseases, the NMDA receptor-mediated excitotoxicity may be of a slower process. For these reasons, NMDA receptors have been pursued with the goal of designing new therapeutic strategies for a number of diseases. However, these efforts have been severely hampered by the lack of subunit selective ligands, which has so far only been developed for NR2B (e.g. ifenprodil).

Project
In the current project it is the aim to develop NR3-subunit selective ligands for the NMDA receptor in order to facilitate subsequent delineation of the physiological roles and therapeutic prospects of NR3-containing NMDA receptors. So far the only truly NMDA receptor subunit selective ligands have been allosteric modulators such as the non-competitive antagonist ifenprodil, which binds outside of the conserved orthosteric binding pocket.

Several approaches will be pursued in the development of such ligands. First approach regards the functional screening of ligand libraries at NMDA receptors based on a virtual screen. Once the screening is completed we will characterize the pharmacological profile of the most interesting hits with regard to their potency, efficacy, and selectivity profiles. In addition, we will make an initial structure-activity relationship (SAR) profile by purchase of analogs. The most interesting compounds that come out of the screening and initial SAR analysis will be subject to in-house medicinal chemistry efforts in order to further improvement of the pharmacological profile. In addition we will use molecular pharmacological tools (e.g. mutations and sophisticated electro-physiological methods) in order to delineate the molecular mode-of-action of the novel compounds.

Perspective
The goal of the project is to develop novel pharmacological tools, which can subsequently be used in vitro, ex vivo and in vivo to elucidate the physiological function of the individual NMDA receptor subtypes. Given the important roles of NMDA receptors in (pato)physiology, the ligands might serve as leads and inspiration to develop novel therapeutic agents in a longer perspective.

Main-advisor:
Hans Bräuner-Osborne

Co-advisors:
Kasper Bø Hansen

Kaae BH, Harpsøe K, Kvist T, Mathiesen JM, Mølck C, Gloriam DE, Jimenez HN, Uberti MA, Nielsen SM, Nielsen B, Bräuner-Osborne H, Sauerberg P, Clausen RP, Madsen U. Structure-activity relationships for negative allosteric mGluR5 modulators. ChemMedChem. 2012, 7; 440-51.

Pan Y, Gerasimov MR, Kvist T, Wellendorph P, Madsen KK, Pera E, Lee H, Schousboe A, Chebib M, Bräuner-Osborne H, Craft CM, Brodie JD, Schiffer WK, Dewey SL, Miller SR, Silverman RB. (1S,3S)-3-amino-4-difluoromethylenyl-1-cyclopentanoic acid (CPP-115), a potent g-aminobutyric acid aminotransferase inactivator for the treatment of cocaine addiction. J Med Chem, 2012, 55; 357-66.

Kvist T, Hansen KB, Braüner-Osborne H. The use of Xenopus oocytes in drug screening. Expert Opin Drug Discov, 2011, 6; 141-53.

Stanley NJ, Pedersen DS, Nielsen B, Kvist T, Mathiesen JM, Bräuner-Osborne H, Taylor DK, Abell AD. Towards 1,2,3-Triazolyl amino acids as AMPA receptor ligands. Bioorg Med Chem Lett. 2010, 20(24); 7512-5.

Stanley NJ, Hutchinson MR, Kvist T, Nielsen B, Mathiesen JM, Bräuner-Osborne H, Avery TD, Tiekink ERT, Pedersen DS, Irvine RJ, Abell AD, Taylor DK. A new metabotropic glutamate recepor agonist with in vivo anti-allodynic activity. Bioorg Med Chem. 2010, 18(16); 6089-98.

Hansen KB, Mullasseril P, Dawit S, Kurtkaya NL, Yuan H, Vance KM, Orr AG, Kvist T, Ogden KK, Le P, Vellano KM, Lewis L, Kurtkaya S, Du Y, Qui M, Murphy TJ, Snyder JP, Bräuner-Osborne H, and Traynelis SF. Implementation of a fluorescence-based screening assay identifies histamine H3 receptor antagonists as subunit-selective NMDA receptor antagonists. J Pharmacol Exp Ther. 2010, 333(3); 650-62.

Kvist T*, Christiansen B* (co-first-auther), Jensen AA, and Bräuner-Osborne H. The four human g-aminobutyric acid (GABA) transporters: pharmacological characterization and validation of a highly efficient screening assay. Comb Chem High Throughput Screen. 2009, 12(3); 241-9.    

Christiansen B*, Kvist T* (co-first-auther), Jensen AA, and Bräuner-Osborne H. The human g-aminobutyric acid transporter GAT-2: from cloning to high throughput screening (J. Olesen and N. Ramadan, eds.). In: Innovative drug development for headache disorders. Frontiers in Headache Research, Vol. 16. Oxford University Press (Oxford, UK). 3-15 (2008).

Christiansen B, Kvist T, Jensen AA, and Bräuner-Osborne H. En ny human GABA transportør. Lægemiddelforskning 2008. P 25-27 (2008)