Glutamate is the main excitatory neurotransmitter in central nervous system (CNS) and NMDA receptors are one of the major classes of ionotropic glutamate receptors. NMDA receptors have been known to play critical roles in normal CNS activities, as well as in many pathological conditions, including both acute and chronic diseases. The discovery of glycine as a coagonist of NMDA receptors has led to intensive research of glycine/NMDA antagonists as potential CNS drugs. The robust efficacy of glycine/NMDA antagonists, such as ACEA-1021 (5), in animal model of brain ischemia, together with good safety profile in animal models and in clinical trials, suggested that this class of NMDA antagonists should have good chance of success in the clinic as neuroprotectants. The clinical trial of ACEA-1021 for stroke was discontinued, mainly due to low solubility and lack of metabolism of the drug that led to the observation of crystals in the urine of some of the patients. However, through SAR studies, compounds such as ACEA-1416 (10) have been identified with improved properties, such as higher in vivo potency and site for potential metabolism. Therefore these compounds should be able to overcome some of the liabilities of ACEA-1021 and potentially could be developed as neuroprotectants. Based on the preclinical and clinical studies of glycine/NMDA antagonists, as well as the clinical experiences with t-PA, initiation of treatment within a short time window after the onset of stroke could be critical for the success of these antagonists in clinical trials. This can be accomplished by implementing the procedure developed for t-PA clinical trials, with modification based on the safety profile of glycine/NMDA antagonists, for future clinical trial to administer the drug as soon as possible after stroke onset. In addition, glycine/NMDA antagonists also have other potential therapeutic applications, such as for the treatment of traumatic brain injury, pain, cocaine overdose and convulsions.

01 Dec 2004·CNS Drug Reviews

ACEA 1021: Flip or Flop?

Review

Author: Philip M. Weintraub ; Kenneth I. Maynard ; Margaret A. Petty

ABSTRACTInasmuch as glutamate is the main excitatory neurotransmitter in the central nervous system, strategies aimed at counteracting glutamate excitotoxicity, which is at least partially involved in many acute neurologic, chronic neurodegenerative and psychiatric diseases, are challenging. Blockade of the NMDA receptor was identified as one way of achieving selective antagonism and overcoming glutamate neurotoxicity, yet not without liabilities. Glycine site antagonism of the NMDA receptor in 1987 offered a significant advance in blocking this receptor because such drugs were shown to lack most of the side effects, such as memory impairment, ataxia, lack of motor coordination and psychotomimetic effects, which accompanied competitive and non‐competitive NMDA receptor antagonists. To date, much has been done to improve the structure‐activity relationship (SAR) of compounds resulting in the synthesis of ACEA 1021. It is unclear, however, whether further chemical substitutions will lead to an improved compound. Many studies have been performed with ACEA 1021 and although there are much in vitro and in vivo data to support its neuroprotective effects and improved safety profile, there is very little published information regarding its clinical pharmacology. In order to properly evaluate the true potential for ACEA 1021 in acute and chronic CNS disorders additional longer term safety and efficacy data in humans are needed.

01 May 2004·Life SciencesQ3 · MEDICINE

Effects of modulators of N-methyl-D-aspartate receptor-mediated neurotransmission on diazepam discrimination in rats

Q3 · MEDICINE

Article

Author: Balster, Robert L. ; Wiley, Jenny L.

N-methyl-D-aspartate (NMDA) antagonists share a number of pharmacological effects with GABA(A) agonists, including anxiolytic and anticonvulsant effects. This study evaluated the effects of site-selective NMDA antagonists in rats trained to discriminate the benzodiazepine diazepam from vehicle. As expected, diazepam produced robust discriminative stimulus effects and dose-dependently substituted for the training dose. Mixed results were obtained with competitive NMDA antagonists: whereas NPC 17742 partially substituted for diazepam, SDZ EAA 494 did not elicit responding on the diazepam-associated lever. Other site-selective NMDA antagonists, including the open channel blocker phencyclidine, the glycine-site antagonists ACEA 1021 and MDL 102,288, the polyamine-site antagonist arcaine, and the glutamate release inhibitor riluzole, failed to substitute for diazepam. Agonists at nonbenzodiazepine sites of the GABA(A) receptor complex were also tested for comparison purposes. The barbiturate pentobarbital and the neurosteroid Co 2-1068 partially substituted for diazepam. In contrast, the anticonvulsant carbamazepine failed to substitute even at a dose that substantially reduced response rates. These results suggest that substitution of NMDA antagonists for GABA(A) agonists is dependent upon the site at which the NMDA antagonist binds. Further, they suggest that similarities between the stimulus properties of GABA(A) agonists and NMDA antagonists are at least as strong as similarities among agonists acting at different sites on GABA(A) receptors.

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KEGG	Wiki	ATC	Drug Bank
D04728	Licostinel	-	-

R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Craniocerebral Trauma	Phase 1	-	Novartis Corp.	29 Apr 1997
Stroke	Phase 1	US	CoCensys, Inc.	29 Apr 1997

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