The competitive NMDA receptor antagonist SDZ 220-581 reverses haloperidol-induced catalepsy in rats.
The present studies investigated whether SDZ 220-581 ((S)-alpha-amino 2'chloro-5-(phosphonomethyl)[1,1'-biphenyl]-3-propanoic acid), a potent, competitive antagonist at the NMDA glutamate receptor subtype, reversed haloperidol-induced catalepsy in rats, a widely used model of Parkinson's disease. SDZ 220-581 (0.32-3.2 mg/kg i.p.) dose- and time-dependently reduced the time spent in an abnormal position induced by haloperidol (1.0 mg/kg s.c.). Compared to other NMDA receptor antagonists the rank order of potency was MK-801 ((+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine) > SDZ 220-581 > SDZ EAA 494 (D-CPPene: (S)-(E)-4-(3-phosphonoprop-2-enyl)-piperazine-2-carboxylic acid) > SDZ EAB 515 ((S)-alpha-amino-5-(phosphonomethyl)[1,1'-biphenyl]-3-propanoic acid). Since it has been demonstrate that SDZ 220-581 counters the effects of L-dihydroxyphenylalanine (L-DOPA) on the motor disturbances of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-pre-treated primates, the results suggest that the reversal of haloperidol-induced catalepsy by competitive NMDA receptor antagonists may not be predictive of efficacy in other models of Parkinson's disease.
McAllister
K H
KH
Sandoz Research Institute Berne Ltd., Berne, Switzerland.
D000818:Animals; D014150:Antipsychotic Agents / Q000037:antagonists & inhibitors*; D001667:Binding, Competitive; D001713:Biphenyl Compounds / Q000737:chemistry / Q000494:pharmacology*; D002375:Catalepsy / Q000139:chemically induced / Q000188:drug therapy*; D016291:Dizocilpine Maleate / Q000737:chemistry / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000737:chemistry / Q000494:pharmacology*; D006220:Haloperidol / Q000037:antagonists & inhibitors*; D008297:Male; D015394:Molecular Structure; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D011422:Propionates / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D018709:Statistics, Nonparametric; D013329:Structure-Activity Relationship
D014150:Antipsychotic Agents; D001713:Biphenyl Compounds; D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D011422:Propionates; D016194:Receptors, N-Methyl-D-Aspartate; C104918:alpha-amino-2'-chloro-5-(phosphonomethyl)(1,1'-biphenyl)-3-propanoic acid; D016291:Dizocilpine Maleate; D006220:Haloperidol