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.
We examined the effects of novel tricyclic quinoxalinedione derivatives, SM-18400 ((S)-9-chloro-5-[p-aminomethyl-o-(carboxymethoxy)phenylcarbamoylmethy l]-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.
Maruoka
Y
Y
Discovery Research Laboratories II, Research Center, Sumitomo Pharmaceuticals Co., Ltd., Osaka, Japan.
Ohno
Y
Y
Tanaka
H
H
Yasuda
H
H
Otani
K
K
Tamamura
C
C
Nakamura
M
M
D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D066298:In Vitro Techniques; D007736:Kynurenic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D011810:Quinoxalines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000502:physiology; D012018:Reflex / Q000187:drug effects / Q000502:physiology; D012694:Serine / Q000494:pharmacology; D013116:Spinal Cord / Q000187:drug effects* / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology
D000634:Aminoquinolines; D018691:Excitatory Amino Acid Antagonists; C113034:ID 17263; C113035:ID 17332; D011810:Quinoxalines; D016194:Receptors, N-Methyl-D-Aspartate; C113033:SM 18400; C074617:4-trans-2-carboxy-5,7-dichloro-4-phenylaminocarbonylamino-1,2,3,4-tetrahydroquinoline; D012694:Serine; D007736:Kynurenic Acid; C066192:5,7-dichlorokynurenic acid