Anticonvulsant activity of a mGlu(4alpha) receptor selective agonist, (1S,3R,4S)-1-aminocyclopentane-1,2,4-tricarboxylic acid.

Abstract

The metabotropic Group III agonist, (1S,3R,4S)-1-aminocyclopentane-1,2,4-tricarboxylic acid (ACPT-1), selective for the mGlu(4alpha) receptor, suppresses sound-induced seizures in DBA/2 mice following its intracerebroventricular (i.c.v.) administration (ED(50) 5.6 [2.9-10.7], nmol i.c.v., 15 min, clonic phase) and in genetically epilepsy-prone (GEP) rats following focal administration into the inferior colliculus (ED(50) 0.08 [0.01-0.50], nmol, 60 min, clonic phase). ACPT-1 also protects against clonic seizures induced in DBA/2 mice by the Group I agonist, (RS)-3,5-dihydroxyphenylglycine (3,5-DHPG) (ED(50) 0.60 [0.29-1.2], nmol i.c.v.) and by the Group III antagonist, (RS)-alpha-methylserine-O-phosphate (MSOP) (ED(50) 49.3 [37.9-64.1], nmol i.c.v.). Another Group III agonist, (RS)-4-phosphonophenyl-glycine (PPG), preferentially activating the mGlu(8) receptor, previously shown to protect against sound-induced seizures in DBA/2 mice and GEP rats, also protects against seizures induced in DBA/2 by 3,5-DHPG (ED(50) 3.7 [2.4-5.7], nmol i.c.v.) and by the Group III antagonist, MSOP (ED(50) 40.2 [21.0-77.0], nmol i.c.v.). At very high doses (500 nmol i.c.v. and above), Group III antagonists have pro-convulsant and convulsant activity. The anticonvulsant protection against sound-induced seizures in DBA/2 mice provided by a fully protective dose (20 nmol, i.c.v.) of the mGlu(4) receptor agonist ACPT-1, is partially reversed by the co-administration of the Group III antagonists, MSOP, (RS)-alpha-methyl-4-phosphonophenylglycine (MPPG) or (S)-2-amino-2-methyl-4-phosphonobutanoic acid (MAP4), in the 20-50 nmol dose range. At doses of 50-200 nmol, MPPG and MAP4 cause further reversal of the ACPT-1 anticonvulsant protection, while the MSOP effect on ACPT-1 protection is abolished at higher doses. In contrast, the anticonvulsant protection against sound-induced seizures in DBA/2 mice provided by a fully protective dose (20 nmol, i.c.v.) of the mGlu(8) receptor agonist PPG, is not significantly affected by the co-administration of the same Group III antagonists, MSOP, MPPG or MAP4. We conclude that activation of either mGlu(4alpha) or mGlu(8) receptors confer anticonvulsant protection in DBA/2 mice. Furthermore, the metabotropic Group III receptor antagonists, MSOP, MPPG, and MAP4 appear to be functionally selective for the mGlu(4) receptor in this system.

• Authors: A G Chapman, A Talebi, P K Yip, B S Meldrum
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 424 Issue 2 Pg. 107-13 (Jul 20 2001) ISSN: 0014-2999 [Print] Netherlands
• PMID: 11476756 (Publication Type: Journal Article)

Chemical References

• 1-aminocyclopentane-1,2,4-tricarboxylic acid
• 2-amino-2-methyl-4-phosphonobutyrate
• 4-phosphonophenylglycine
• Aminobutyrates
• Anticonvulsants
• Cyclopentanes
• Excitatory Amino Acid Agonists
• Excitatory Amino Acid Antagonists
• Receptors, Metabotropic Glutamate
• Resorcinols
• Tricarboxylic Acids
• alpha-methyl-4-phosphonophenylglycine
• methylserine phosphate
• Phosphoserine
• 3,5-dihydroxyphenylglycine
• Alanine
• Glycine
• metabotropic glutamate receptor 4

Topics

• Acoustic Stimulation
• Alanine (analogs & derivatives, pharmacology)
• Aminobutyrates (pharmacology)
• Animals
• Anticonvulsants (pharmacology)
• Behavior, Animal (drug effects)
• Cyclopentanes (pharmacology)
• Dose-Response Relationship, Drug
• Excitatory Amino Acid Agonists (pharmacology)
• Excitatory Amino Acid Antagonists (pharmacology)
• Female
• Glycine (analogs & derivatives, pharmacology)
• Injections, Intraventricular
• Male
• Mice
• Mice, Inbred DBA
• Phosphoserine (pharmacology)
• Psychomotor Performance (drug effects)
• Rats
• Receptors, Metabotropic Glutamate (agonists, antagonists & inhibitors)
• Resorcinols (pharmacology)
• Seizures (etiology, genetics, prevention & control)
• Tricarboxylic Acids (pharmacology)