The glycine/NMDA receptor ligand (+)-HA-966 but not D-cycloserine has potent antidystonic efficacy in a genetic animal model of dystonia.
The effects of R-(+)-HA-966 ((+)-3-amino-1-hydroxypyrrolid-2-one), a low-efficacy partial agonist of the glycine modulatory site of the NMDA receptor complex, were studied in an inbred line of Syrian golden hamsters with generalized dystonia, a frequent movement disorder in humans. The effects of R-(+)-HA-966 were compared with those of D-cycloserine, a glycine/NMDA receptor ligand with higher intrinsic activity. R-(+)-HA-966, 30-60 mg/kg i.p., potently reduced the severity of dystonic attacks in the mutant hamster model of dystonia without inducing any behavioural adverse effects. D-Cycloserine did not exert antidystonic activity at i.p. doses of 10-40 mg/kg, which might be due to its much higher intrinsic activity at the glycine site. The data indicate that the antidystonic effect of (+)-HA-966 is related to antagonism of NMDA receptor-mediated excitatory neurotransmission.
Löscher
W
W
Department of Pharmacology, Toxicology and Pharmacy, School of Veterinary Medicine, Hannover, Germany.
Richter
A
A
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D006224:Cricetinae; D003523:Cycloserine / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004421:Dystonia / Q000188:drug therapy* / Q000235:genetics; D005260:Female; D005998:Glycine / Q000378:metabolism; D008297:Male; D008647:Mesocricetus; D011760:Pyrrolidinones / Q000494:pharmacology* / Q000627:therapeutic use; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013237:Stereoisomerism; D009435:Synaptic Transmission / Q000187:drug effects
D011760:Pyrrolidinones; D016194:Receptors, N-Methyl-D-Aspartate; D003523:Cycloserine; C001369:1-hydroxy-3-amino-2-pyrrolidone; D005998:Glycine