Many agents that antagonize the NMDA receptor-channel complex in vivo also cause disturbances of motor coordination

Antagonists of the NMDA receptor-channel complex may be useful for the treatment of thrombotic stroke, head injury and epilepsy. Their clinical use, however, could be limited by the incidence of side effects such as ataxia. I have therefore investigated the relationship between functional antagonism of the N-methyl-D-aspartate (NMDA) receptor-channel complex in vivo and disturbances of motor coordination. Antagonism of the NMDA receptor-channel complex was assessed by measuring a compounds ability to inhibit NMDA-induced lethality in mice, disturbances of motor coordination were measured by the rotarod technique. NMDA dose-dependently induced convulsions and ultimately caused death in mice (LD50 = 137 +/- 4 mg/kg i.p.). Noncompetitive NMDA antagonists of either an arylcyclohexylamine (phencyclidine, (+)/(-)-MK-801 [10-11-dihydro-5-methyl-5H-dibenzo[a,d] cyclohepten-5,10-imine hydrogen maleate] and ketamine) or a benzomorphan (dextrorphan and N-allylnormetazocine) structure, competitive antagonists (CGP 37849 [(R,S)-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid monohydrate] and CGP 39551 [(R,S)-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid 1-ethyl ester]) or a glycine site antagonist (L-687,414 [(3R,4R)-3-amino-4-methyl-1-hydroxy-pyrrolidin-2-one-(-)-tartrate salt]) inhibited NMDA-induced lethality after s.c. administration. These compounds also interfered with motor coordination. There was an excellent correlation (r = 0.97) between the two effects.(ABSTRACT TRUNCATED AT 250 WORDS)