Abstract

The immediate objectives of the program are to synthesize and characterize new pharmacological tools for the study of excitatory amino acid transmitter systems in the brain, to use these new agents (and preexisting substances) to advance knowledge of central excitatory amino acid transmitter systems, and to design and synthesize new drugs with defined actions on these transmitter systems for the treatment of neurological and/or psychiatric disorders. New excitatory amino acid agonists and antagonists will be synthesized and their actions characterized by well-proven screening techniques including electrophysiological testing in vitro (isolated rat spinal cord and hippocampal slices) and in vivo (cat spinal cord and brain) as well as radioligand binding techniques on rat brain membranes. Drug potential will be assessed in a number of collaborative ventures and will include tests on mice and rats for anticonvulsant, muscle relaxant and anxiolytic properties, and the ability of the substances to prevent ischemic and other types of neuronal degeneration. Associated projects will include the synthesis of potential uptake blockers of excitatory amino acids, new agents for the preparation of affinity chromatography ligands, the biosynthesis of sulfur-contain% amino acids, and the chemical and pharmacological characterization of a brain fraction with pronounced neuro-depressant activity.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS026540-05
Application #
3412467
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1988-07-15
Project End
1994-06-30
Budget Start
1992-07-01
Budget End
1993-06-30
Support Year
5
Fiscal Year
1992
Total Cost
Indirect Cost

  Institution

Name
University of Bristol
Department
Type
DUNS #
City
Bristol
State
Country
United Kingdom
Zip Code
BS8 1-TH

  Publications

Sekiyama, N; Hayashi, Y; Nakanishi, S et al. (1996) Structure-activity relationships of new agonists and antagonists of different metabotropic glutamate receptor subtypes. Br J Pharmacol 117:1493-503
Thompson, G A; Jones, P L; Kilpatrick, I C (1995) The actions of a range of excitatory amino acids at (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid-depolarizing receptors on neonatal rat motoneurones. Neuropharmacology 34:857-63
Roberts, P J (1995) Pharmacological tools for the investigation of metabotropic glutamate receptors (mGluRs): phenylglycine derivatives and other selective antagonists--an update. Neuropharmacology 34:813-9
Kemp, M; Roberts, P; Pook, P et al. (1994) Antagonism of presynaptically mediated depressant responses and cyclic AMP-coupled metabotropic glutamate receptors. Eur J Pharmacol 266:187-92
Hayashi, Y; Sekiyama, N; Nakanishi, S et al. (1994) Analysis of agonist and antagonist activities of phenylglycine derivatives for different cloned metabotropic glutamate receptor subtypes. J Neurosci 14:3370-7
Pook, P; Brugger, F; Hawkins, N S et al. (1993) A comparison of the actions of agonists and antagonists at non-NMDA receptors of C fibres and motoneurones of the immature rat spinal cord in vitro. Br J Pharmacol 108:179-84
Eaton, S A; Birse, E F; Wharton, B et al. (1993) Mediation of thalamic sensory responses in vivo by ACPD-activated excitatory amino acid receptors. Eur J Neurosci 5:186-9
Birse, E F; Eaton, S A; Jane, D E et al. (1993) Phenylglycine derivatives as new pharmacological tools for investigating the role of metabotropic glutamate receptors in the central nervous system. Neuroscience 52:481-8
Eaton, S A; Jane, D E; Jones, P L et al. (1993) Competitive antagonism at metabotropic glutamate receptors by (S)-4-carboxyphenylglycine and (RS)-alpha-methyl-4-carboxyphenylglycine. Eur J Pharmacol 244:195-7
Watkins, J C (1991) Some chemical highlights in the development of excitatory amino acid pharmacology. Can J Physiol Pharmacol 69:1064-75

Showing the most recent 10 out of 14 publications