Anticonvulsant actions of LY 367385 ((+)-2-methyl-4-carboxyphenylglycine) and AIDA ((RS)-1-aminoindan-1,5-dicarboxylic acid).
We have studied the effects in three rodent models of generalised convulsive or absence epilepsy of two antagonists of group I metabotropic glutamate receptors that are selective for the mGlu1 receptor. LY 367385 ((+)-2-methyl-4-carboxyphenylglycine) and AIDA ((RS)-1-aminoindan-1,5-dicarboxylic acid) have been administered intracerebroventricularly (i.c.v.) to DBA/2 mice and lethargic mice (lh/lh), and focally into the inferior colliculus of genetically epilepsy prone rats (GEPR). In DBA/2 mice both compounds produce a rapid, transient suppression of sound-induced clonic seizures (LY 367385: ED50 = 12 nmol, i.c.v., 5 min; AIDA: ED50 = 79 nmol, i.c.v., 15 min). In lethargic mice both compounds significantly reduce the incidence of spontaneous spike and wave discharges on the electroencephalogram, from <30 to >150 min after the administration of AIDA, 500 nmol, i.c.v., and from 30 to >150 min after the administration of LY 367385, 250 nmol, i.c.v. LY 367385, 50 nmol, suppresses spontaneous spike and wave discharges from 30 to 60 min. In genetically epilepsy prone rats both compounds reduce sound-induced clonic seizures. LY 367385, 160 nmol bilaterally, fully suppresses clonic seizures after 2-4 h. AIDA is fully effective 30 min after 100 nmol bilaterally. It is concluded that antagonists of mGlu1 receptors are potential anticonvulsant agents and that activation of mGlu1 receptors probably contributes to a variety of epileptic syndromes.
Chapman
A G
AG
Department of Clinical Neurosciences, Institute of Psychiatry, King's College London, De Crespigny Park, Denmark Hill, UK.
Yip
P K
PK
Yap
J S
JS
Quinn
L P
LP
Tang
E
E
Harris
J R
JR
Meldrum
B S
BS
D000161:Acoustic Stimulation / Q000009:adverse effects; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology* / Q000627:therapeutic use; D001565:Benzoates; D004305:Dose-Response Relationship, Drug; D004832:Epilepsy, Absence / Q000209:etiology / Q000235:genetics / Q000517:prevention & control; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D007189:Indans / Q000494:pharmacology* / Q000627:therapeutic use; D007245:Inferior Colliculi / Q000187:drug effects; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D008817:Mice, Mutant Strains; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors; D012640:Seizures / Q000209:etiology / Q000517:prevention & control; D013016:Sound / Q000009:adverse effects
C095756:1-aminoindan-1,5-dicarboxylic acid; D000927:Anticonvulsants; D001565:Benzoates; D018691:Excitatory Amino Acid Antagonists; D007189:Indans; D018094:Receptors, Metabotropic Glutamate; C079694:alpha-methyl-4-carboxyphenylglycine; D005998:Glycine