GlycineB antagonists and partial agonists in rodent models of Parkinson's disease--comparison with uncompetitive N-methyl-D-aspartate receptor antagonist.
Antiparkinsonian-like activity of glutamate receptor antagonists (mostly of N-methyl-D-aspartate (NMDA) receptors) has been demonstrated in animals and for uncompetitive agents, also in humans. In the present study we investigated the potential antiparkinsonian-like activity of compounds acting at the glycine site of the NMDA receptor complex in three animal models of Parkinson's disease and compared them with the new uncompetitive NMDA receptor antagonist MRZ 2/579. Haloperidol-induced catalepsy was inhibited by the Merz glycine site antagonists MRZ 2/570, MRZ 2/571 and MRZ 2/576 but not by another antagonist L-701,324 or the glycine site partial agonists ACPC and D-CS. None of the tested glycine site antagonists or partial agonists increased locomotor activity or potentiated L-DOPA responses in reserpine and alpha-MT treated rats. In rats with a unilateral 6-OHDA medial forebrain bundle lesion neither glycine site antagonists nor partial agonists affected rotations on their own or enhanced the contralateral rotations induced by L-DOPA. In contrast, the uncompetitive NMDA receptor antagonist MRZ 2/579 was active in all antiparkinsonian tests used in this study. Based on the present data the therapeutic potential of the glycine site antagonists and partial agonists tested for the treatment of Parkinson's disease is rather doubtful. Uncompetitive NMDA receptor antagonists seem to possess a better profile as antiparkinsonian agents.
Karcz-Kubicha
M
M
Department of Pharmacological Research, Merz + Co., Frankfurt/Main, Germany.
Lorenz
B
B
Danysz
W
W
D000818:Animals; D000978:Antiparkinson Agents / Q000627:therapeutic use*; D001667:Binding, Competitive; D002375:Catalepsy / Q000139:chemically induced; D003517:Cyclopentanes / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use*; D018684:Glycine Agents / Q000494:pharmacology*; D006220:Haloperidol / Q000633:toxicity; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D007980:Levodopa / Q000494:pharmacology; D008297:Male; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D010302:Parkinson Disease, Secondary / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D012110:Reserpine / Q000494:pharmacology
D000978:Antiparkinson Agents; D003517:Cyclopentanes; D018691:Excitatory Amino Acid Antagonists; D018684:Glycine Agents; D006993:Hypnotics and Sedatives; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; D007980:Levodopa; C114144:neramexane; D012110:Reserpine; D006220:Haloperidol