EFFECTS OF THE NOVEL TRICYCLIC QUINOXALINEDIONE DERIVATIVES, SM-18400AND ITS ANALOGS, ON N-METHYL-D-ASPARTATE (NMDA) RECEPTOR-MEDIATED SYNAPTIC TRANSMISSION IN THE ISOLATED NEONATAL RAT SPINAL-CORD IN-VITRO

We examined the effects of novel tricyclic quinoxalinedione derivative s, SM-18400 ((S)-9-chloro-5-[p-aminomethyl-o-(carboxymethoxy) ihydro-1 H,5H-pyrido[1,2,3-de]quinoxaline-2,3-dione hydrochloride trihydrate) a nd its analogs (i.e., ID-17263 and ID-17332), on the N-methyl-D-aspart ate (NMDA) receptor-mediated polysynaptic reflex (PSR) in the isolated spinal cord of neonatal rats in vitro. Application of SM-18400 select ively suppressed the PSR activity in a concentration-dependent manner without affecting the monosynaptic reflex (MSR). Differential suppress ion of the PSR was also obtained with ID-17263, ID-17332 and other kno wn NMDA receptor glycine-binding site antagonists,5,7-dichlorokynurena te (5,7-diClkyn) and L-689,560 lamino-carbonylamino-1,2,3,4-tetrahydro quinoline). Relative potencies of the test drugs for inhibition of the PSR were as follows: SM-18400 much greater than L-689,560 > ID-17332 > ID-17263 > 5,7-diClkyn. In addition, the inhibitory effects of SM-18 400 on PSR were markedly antagonized by simultaneous application of D- serine, and agonist for NMDA receptor glycine-binding sites. These fin dings suggest that SM-18400 is a potent NMDA receptor glycine-binding site antagonist and blocks the NMDA receptor-mediated synaptic neurotr ansmission in the spinal cord in vitro.