In vitro and in vivo antagonistic activities of SM-31900 for the NMDA receptor glycine-binding site.
The purpose of this study was to clarify the in vitro pharmacological profile and the in vivo activity of (3S)-7-chloro-3-[2-((1R)-1-carboxyethoxy)-4-aminomethylphenyl]aminocarbonylmethyl-1,3,4,5-tetrahydrobenz[c,d]indole-2-carboxylic acid hydrochloride (SM-31900). SM-31900 inhibited the binding of [3H]glycine and [3H]5,7-dichlorokynurenic acid, radioligands for the N-methyl-D-aspartate (NMDA) receptor glycine-binding site, to rat brain membranes in a competitive manner, with K(i) values of 11+/-2 and 1.0+/-0.1 nM, respectively, and completely prevented the binding of [3H]dizocilpine (MK-801), a radioligand for the NMDA receptor channel site. In cultures of rat cortical neurons, SM-31900 markedly prevented the neuronal cell death induced by transient exposure to glutamate, in a concentration-dependent manner. Its neuroprotective potency was much stronger than those of other glycine-binding site antagonists (4-trans-2-carboxy-5,7-dichloro-4-phenylaminocarbonylamino-1,2,3,4-tetrahydroquinoline (L-689,560), 5,7-dichlorokynurenic acid, and 7-chlorokynurenic acid). Furthermore, SM-31900 showed anticonvulsant activity when administered systemically, unlike other antagonists. These data indicate that SM-31900 is a systemically active antagonist with high affinity for the NMDA receptor glycine-binding site.
Ohtani
Ken-ichi
K
Research Center, Sumitomo Pharmaceuticals Co., Ltd, Osaka, Japan. ohtani@sumitomopharm.co.jp
Tanaka
Hiroyasu
H
Yoneda
Yukio
Y
Yasuda
Hirokazu
H
Ito
Akira
A
Nagata
Ryu
R
Nakamura
Mitsutaka
M
D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005333:Fetus; D018698:Glutamic Acid / Q000378:metabolism* / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology*; D007736:Kynurenic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009498:Neurotoxins / Q000378:metabolism*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D018009:Receptors, Glycine / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012640:Seizures / Q000188:drug therapy*
D000634:Aminoquinolines; D018691:Excitatory Amino Acid Antagonists; D007211:Indoles; D018696:Neuroprotective Agents; D009498:Neurotoxins; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate; C466317:SM 31900; C074617:4-trans-2-carboxy-5,7-dichloro-4-phenylaminocarbonylamino-1,2,3,4-tetrahydroquinoline; D018698:Glutamic Acid; D016291:Dizocilpine Maleate; D007736:Kynurenic Acid; C057013:7-chlorokynurenic acid; C066192:5,7-dichlorokynurenic acid