Effects of the Novel Tricyclic Quinoxalinedione Derivatives, SM-18400 and Its Analogs, on N-Methyl-D-aspartate (NMDA) Receptor-Mediated Synaptic Transmission in the Isolated Neonatal Rat Spinal Cord In Vitro

Abstract

We examined the effects of novel tricyclic quinoxalinedione derivatives, SM-18400 ((S)-9-chloro-5-[p-aminomethyl-o-(carboxymethoxy)phenylcarbamoylmethyl]-6, 7-dihydro-1H, 5H-pyrido[1, 2, 3-de]quinoxaline-2, 3-dione hydrochloride trihydrate) and its analogs (i.e., ID-17263 and ID-17332), on the N-methyl-D-aspartate (NMDA) receptor-mediated polysynaptic reflex (PSR) in the isolated spinal cord of neonatal rats in vitro. Application of SM-18400 selectively suppressed the PSR activity in a concentration-dependent manner without affecting the monosynaptic reflex (MSR). Differential suppression of the PSR was also obtained with ID-17263, ID-17332 and other known NMDA receptor glycine-binding site antagonists, 5, 7-dichlorokynurenate (5, 7-diClkyn) and L-689, 560 (4-trans-2-carboxy-5, 7-dichloro-4-phenylaminocarbonylamino-1, 2, 3, 4-tetrahydroquinoline). Relative potencies of the test drugs for inhibition of the PSR were as follows: SM-18400 >> L-689, 560 > ID-17332 > ID-17263 > 5, 7-diClkyn. In addition, the inhibitory effects of SM-18400 on PSR were markedly antagonized by simultaneous application of D-serine, an agonist for NMDA receptor glycine-binding sites. These findings suggest that SM-18400 is a potent NMDA receptor glycine-binding site antagonist and blocks the NMDA receptor-mediated synaptic neurotransmission in the spinal cord in vitro.