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

Maruoka, Yoshimi; Ohno, Yukihiro; Tanaka, Hiroyasu; Yasuda, H; Otani, Ken-ichi; Tamamura, Chika; Nakamura, Mitsutaka

doi:10.1254/jjp.76.265

Cited by 9 publications

(1 citation statement)

References 15 publications

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“…SM-18400 showed excellent selectivity with > 10,000-fold over 50 receptors and enzymes including the glutamate binding site of the NMDA receptor, AMPA receptors and strychninesensitive glycine receptor. As expected from the strong anticonvulsant activity in the NMDA induced seizure model, SM-18400 was also proven to be an excellent neuroprotectant by experiments using several ischemic models [61][62][63][64] including a bilateral carotid artery occlusion model in spontaneously hypertensive rats (SHR-BCAo model) [63] as shown in Fig. (2) and a middle cerebral artery occlusion model in rats (MCAo model) [64].…”

Section: S 5rmentioning

confidence: 99%

Tricyclic Quinoxalinediones, Aza-kynurenic Acids, and Indole-2- Carboxylic Acids as In Vivo Active NMDA-Glycine Antagonists

Nagata¹,

Katayama²,

Ohtani³

et al. 2006

CTMC

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This review article describes the development of in vivo active antagonists for the glycine binding site of the N-Methyl-D-Aspartate (NMDA) receptor. There were several difficulties in identifying a class of antagonists with in vivo efficacy and only a few compounds succeeded in emerging with activity in vivo. A series of tricyclic quinoxalinediones was highly potent glycine antagonists in vitro and the derivatives having a zwitterionic moiety including SM-18400 indeed showed in vivo activity. Similarly, tricyclic indole-2-carboxylic acids having a zwitterionic moiety such as SM-31900 were also active in vivo. In fact, SM-18400 and SM-31900 exhibited efficacy in several animal stroke models using intravenous infusion protocols. The practical syntheses of SM-18400 and SM-31900 as well as the novel synthesis of moderately active glycine antagonists, tricyclic azakynurenic acids, were also developed.

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Section: S 5rmentioning

confidence: 99%

Tricyclic Quinoxalinediones, Aza-kynurenic Acids, and Indole-2- Carboxylic Acids as In Vivo Active NMDA-Glycine Antagonists

Nagata¹,

Katayama²,

Ohtani³

et al. 2006

CTMC

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Pharmacokinetics of a novelN-methyl-D-aspartate receptor antagonist (SM-18400): Identification of anN-acetylated metabolite and pre-clinical assessment ofN-acetylation polymorphism

Yabuki

Kon-Ya

Kataoka

et al. 2003

Eur. J. Drug Metab. Pharmacokinet.

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(S)-9-chloro-5-[p-aminomethyl-o-(carboxymethoxy)phenylcarbamoylmethyl]-6,7-dihydro-1 H,5 H-pyrido[1,2,3-de]quinoxaline-2,3-dione hydrochloride trihydrate (SM-18400) was given intravenously to rats and dogs and its pharmacokinetics was investigated. By LC/MS/MS analysis, the major metabolite in the rat serum was identified as N-acetylated SM-18400 (SM-NAc). In rats, AUC ratio of SM-NAc to SM-18400 was approximately 50%. However, 71% of the dose was excreted as unchanged SM-18400 and only 9.8% as SM-NAc in the urine and bile, indicating that the contribution of N-acetylation clearance (CL(NAc)) to the total clearance (CL(tot)) is limited to 10-30% in rats. No SM-NAc or other metabolites were detected in the dog serum, urine or bile. The in vitro intrinsic clearance (CL(int), ml/min/mg cytosolic protein) of N-acetyltransferase (NAT) activities of dog liver cytosol towards SM-18400 and hepatic N-acetylation clearance (CL(NAc), ml/min/kg body weight) estimated by well-stirred model were both only 5% of the respective rat value, well reflecting the relative in vivo CL(NAc)/CL(tot) ratios. CL(int) values for human liver cytosol samples (n = 4) and estimated CL(NAc) were all less than 18% and 7% of the rat, respectively. Based on these results, we concluded that the CL(NAc)/CL(tot) of human would be small enough to avoid major inter-individual variance in SM-18400 pharmacokinetics due to N-acetylation polymorphism. In addition, even a human liver cytosol sample lacking polymorphic NAT2 activity as determined by sulfamethazine (SMZ) N-acetylation analysis, proved capable of acetylating SM-18400, suggesting that NAT2 is not the major enzyme responsible for N-acetylation of SM-18400 in human. This fact would also reduce the risk of N-acetylation polymorphism playing a role in clinical use of this drug.

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Effects of morphine and endomorphins on the polysynaptic reflex in the isolated rat spinal cord

Tao¹,

Lai²,

Chow

et al. 2004

Naunyn-Schmiedeberg's Arch Pharmacol

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At the spinal level, mu-opioids exert their actions on nociceptive primary afferent neurons both pre- and postsynaptically. In the present study, we used an in vitro isolated neonatal rat (11-15 days old) spinal cord preparation to examine the effects of morphine and the endogenous mu-opioid ligands endomorphin-1 (EM-1) and endomorphin-2 (EM-2) on the polysynaptic reflex (PSR) of dorsal root-ventral root (DR-VR) reflex. The actions of mu-opioids on spinal nociception were investigated by quantification of the firing frequency and the mean amplitude of the PSR evoked by stimuli with 20 x threshold intensity. EM-1 decreased the mean amplitude of PSR, whereas EM-2 and morphine decreased the firing frequency. The pattern of the effects elicited by morphine was the same as that for EM-2, except at high concentration. Naloxonazine, a selective mu(1) opioid receptor antagonist, had no significant effect on PSR by itself, but blocked the inhibition of PSR firing frequency or amplitude induced by EM-1, -2 and morphine. This may suggest that EM-1, EM-2 and morphine modulate spinal nociception differently and act mainly at the mu(1)-opioid receptors. Although they all act via mu(1)-opioid receptors, their different effects on the PSR may suggest the existence of different subtypes of the mu(1)-opioid receptor. The present data is also consistent with a further hypothesis, namely, that morphine and EM-2 activate a subtype of mu(1)-opioid receptor presynaptically, while EM-1 acts mainly through another subtype postsynaptically. However, since other reports indicate that EM-2, but not EM-1, could stimulate the release of enkephalins or dynorphin, presynaptic delta and kappa receptors may be also involved indirectly in the different regulation by mu-opioids at the spinal level.

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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

Cited by 9 publications

References 15 publications

Tricyclic Quinoxalinediones, Aza-kynurenic Acids, and Indole-2- Carboxylic Acids as In Vivo Active NMDA-Glycine Antagonists

Tricyclic Quinoxalinediones, Aza-kynurenic Acids, and Indole-2- Carboxylic Acids as In Vivo Active NMDA-Glycine Antagonists

Pharmacokinetics of a novelN-methyl-D-aspartate receptor antagonist (SM-18400): Identification of anN-acetylated metabolite and pre-clinical assessment ofN-acetylation polymorphism

Effects of morphine and endomorphins on the polysynaptic reflex in the isolated rat spinal cord

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