Yoshimi Maruoka, Yukihiro Ohno (*), Hiroyasu Tanaka, Hirokazu Yasuda,
Ken-ichi Otani, Chika Tamamura and Mitsutaka Nakamura
Discovery Research Laboratories II, Research Center, Sumitomo Pharmaceuticals
Co., Ltd., Konohana-ku, Osaka 554, Japan
(*) To whom all correspondence should be addressed.
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-phenylamino-carbonylamino-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.
Keywords: SM-18400, NMDA receptor, Glycine-binding site, D-Serine, Spinal
reflex (in vitro)