Pharmacology of Metabotropic Glutamate Receptors : Their Role in Physiology and Pathology

Objective

To examine the role of each metabotropic glutamate receptor (mGluR) subtype in physiology To examine the role of each mGluR subtype in selected neuropathological models . To develop selective agonists and antagonists of mGluRs.

Functional properties of neuronal populations expressing diverse mGluR subtypes will be studied by utilising electrophysiological, biochemical and anatomical techniques. The presynaptic mechanisms whereby mGluR subtypes control neurotransmitter release or the activity of ligand-gated or voltage-operated channels will be evaluated. Molecular biology studies with mGluR chimeras or transfected cells expressing mGluRs will identify critical domains responsible for their specific properties. Finally, attempts to correlate electrophysiological observations with behavioural tasks will also be performed.
Gene expression, pharmacology and electrophysiology of mGluRs will be studied in models of cerebral ischemia in vitro and in vivo and in epilepsy. Behavioural (motor and learning), electrophysiological and biochemical abnormalities will be evaluated in transgenic mice lacking specific mGluRs and in animals treated with antisense oligonucleotides directed against mGluR mRNAs or with selective mGluR subtype antagonists, when developed. We expect to clarify the role played by mGluRs in these pathologies, and whether their activation or blockade might become potentially useful in clinical practice.
Preliminary experiments indicate that aminoindane dicarboxylates (conformationally restricted analogues of phenylglycines) may selectively interact with mGluR subtypes with IC50S in the micromolar range. These compounds were synthesised and patented by three groups participating in this Project and they will be made available to other groups and tested. Since a higher degree of selectivity and affinity are still needed for mGluR research, in the course of this Project new molecules will be designed, synthesised and studied. Upon completion of the Project, novel pharmacological tools will be made available to the scientific community, as well as molecules which might be developed as drugs.

Programme(s)

• FP4-BIOMED 2 - Specific research, technological development and demonstration programme in the field of biomedicine and health, 1994-1998

Topic(s)

• 1.1 - Pharmacotoxicology

Funding Scheme

CSC - Cost-sharing contracts

Coordinator

UNIVERSITY OF FLORENCE

Address

Viale G. Pieraccini 6
50139 Firenze
Italy

Participants (9)

Centre National de la Recherche Scientifique

France

Address

Ccipe, Rue De La Cardonille
34094 Montpellier

Federal Institute for Neurobiology

Germany

Address

6,Brenneckestrasse 6
39008 Magdeburg

Novo-Nordisk A/S

Denmark

Address

Novo Nordisk Park
2760 Malov

Rijksuniversiteit Utrecht

Netherlands

Address

100,Universiteitsweg
3584 CG Utrecht

Universidad Complutense de Madrid

Spain

Address

S/n,avda. Puerta De Hierro S/n
28040 Madrid

University of Bristol

United Kingdom

Address

University Walk
BS8 1TD Bristol

University of Dublin

Ireland

Address

2 Dublin

University of Dundee

United Kingdom

Address

Ninewells Hospital & Med. School
DD1 9SY Dundee

Università degli Studi di Perugia

Italy

Address

Via Del Liceo 1
06123 Perugia