Neuroscience in Denmark


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General information

Name (center, department, group or other)
Bunch Research Group, University of Copenhagen
Contact name
Lennart Bunch
Contact email
lebu#at#sund#dot#ku#dot#dk
Contact title
Group Leader
Date
4. February 2016
(Last edited: 4. February 2016)

Brief description of research activities

In the BUNCH research group, we work on the rational design and synthesis of novel neuroactive ligands. In focus are new tool compounds for the glutamate receptors (iGluRs and mGluRs) and glutamate transporters (EAATs). Furthermore, development of new synthetic methodology for the synthesis of structurally complex molecules is in focus.

In brief, we have accomplished:

Discovery of the first selective EAAT1 inhibitor UCPH-101/UCPH-102: We have discovered the first class of selective EAAT1 inhibitors together with Anders A. Jensen, University of Copenhagen. Extensive structure-activity-relationship studies were made and the analogs UCPH-101 and UCPH-102 are now commercially available standard tool compounds for EAAT studies.

New subtype selective iGluR ligands: CNG-10100 is a rationally designed broad acting iGluR antagonist. From this molecule several interesting analogs have been designed and synthesized: The compound CNG-10104 is selective for GluK3 and shows the first promising results within a new series of proline analogs which is currently being expanded. Creative approaches to new scaffolds are constantly in focus and a recent such study was just published in ACS Chemical Neuroscience. A substituted quinoxaline-2,3-dione was designed and synthesized and displays a highly interesting binding mode in the iGluR.

New subtype selective mGluR ligands: Recently we have disclosed a new lead structure for potent selective mGluR group III agonists. Also a fully selective mGluR2 agonist (also over mGluR3) is described.

MAO substrates: We have explored the substrate pocket of the MAO-A and MAO-B enzymes. This work is to be developed further when funding can be obtained.

Our new ligands are characterized pharmacologically by our close collaborating partners in Denmark and around the World.

Homepage: http://drug.ku.dk/research/mcr/chemical_neuroscience_group/


Keywords

Discovery of novel pharmacological tools for the Glutamate receptors, Glutamate transporters, GABA receptors, MAO A/B.


Research tools and techniques

Organic chemistry
Medicinal chemistry
In silico studies


Scientific Personnel

No of Associate Professors/Postdocs: 1
No of PhD students: 4
Other: 5

Key references from within the last 5 years

“New 4-Functionalized Glutamate Analogs are Selective Agonists at Metabotropic Glutamate Receptor Subtype 2 (mGlu2) or Selective Agonists at Metabotropic Glutamate Receptor Group III” Huynh, THV; Erichsen, MN; Tora, AS; Goudet, C; Sagot, E; Assaf, Z; Thomsen, C; Brodbeck, R; Stensbøl, TB; Nielsen, B; Pin, JP; Gefflaut, T and Bunch, L* J. Med. Chem. 2016, in press

“New Insights into the Structural-Activity-Relationship of Selective Excitatory Amino Acid Transporter Subtype 1 (EAAT1) Inhibitors UCPH-101 and UCPH-102” Hansen, SW; Erichsen, MN; Huynh, THV; Ruiz, JA; Haym, I; Bjørn-Yoshimoto, WE; Abrahamsen, B; Hansen, J; Storgaard, M; Eriksen, A; Jensen, AA and Bunch, L* ChemMedChem 2016, in press

“Bioavailability and in Vitro Profiling of Selective Excitatory Amino Acid Transporter Subtype 1 (EAAT1) Inhibitor UCPH-102” Haym, I; Huynh, THV; Ruiz, JA; Pedersen, MHF; Gynther, M; Bastlund,JF; Bundgaard, C; Abrahamsen, B; Jensen, AA and Bunch, L* ChemMedChem 2016, in press

“Structure-Activity Relationship Study of Ionotropic Glutamate Receptor Antagonist (2S,3R)-3-(3-Carboxyphenyl)pyrrolidine-2-carboxylic Acid” Krogsgaard-Larsen, N; Storgaard, M; Kristensen, CM; Han, L: Demmer, CS; Nielsen, B; Pickering, DS; Kastrup, JS; Frydenvang, K and Bunch, L* J. Med. Chem. 2015, 58, 6131-6150

“Binding Mode of a Rationally Designed α-Amino Acid Linked Quinoxaline-2,3-dione Analog at the Glutamate Receptor Subtype GluK1” Demmer, CS; Møller, C; Brown, PMGE, Han, L; Pickering, DS; Nielsen, B; Bowie, D; Frydenvang, K; Kastrup, JS and Bunch, L* ACS Chem. Neurosci. 2015, 6, 845-854

“Chemo-Enzymatic Synthesis of New 2,4-Syn-Functionalized (S)-Glutamate Analogues and Structure-Activity-Relationship Studies at Ionotropic Glutamate Receptors and Excitatory Amino Acid Transporters” Assaf, Z; Larsen, AP; Venskutonyte, R; Han, L; Abrahamsen, B; Nielsen, B; Gajhede, M; Kastrup, JS; Jensen, AA; Pickering, DS; Frydenvang, K; Gefflaut, T and Bunch,L* J. Med. Chem. 2013, 56, 1614-1628

“Structure-Activity-Relationship Study of Selective EAAT1 inhibitor UCPH-101 and Absolute Configurational Assignment using Infrared (IR) and Vibrational Circular Dichroism (VCD) Spectroscopy in Combination with Ab Initio Hartree-Fock Calculations” Huynh, THV; Shim, I; Bohr, H; Abrahamsen B; Nielsen, B; Jensen, AA and Bunch, L* J. Med. Chem. 2012, 55, 5403-5412

“Discovery of a New Class of Ionotropic Glutamate Receptor Antagonists by the Rational Design of (2S,3R)-3-(3-Carboxyphenyl)-pyrrolidine-2-carboxylic Acid” Larsen, AM; Venskutonyté, R; Valadés, EA; Nielsen, B; Pickering, DS and Bunch, L* ACS Chem. Neurosci. 2011, 2, 107-114

“Structure-Activity-Relationship Study of First Selective Inhibitor of Excitatory Amino Acid Transporter Subtype 1: 2-Amino-4-(4-methoxyphenyl)-7-(naphthalen-1-yl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (UCPH-101)” Erichsen, MN; Huynh, THV; Abrahamsen, B; Bastlund, JF; Bundgaard, C; Monrad, O; Bekker-Jensen, A; Nielsen, CW; Frydenvang, K; Jensen, AA and Bunch, L* J. Med. Chem. 2010, 53, 7180-7191
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