Strychnine-insensitive glycine site antagonists attenuate a cardiac arrest-induced movement disorder

Matsumoto, Rae R.; Nguyen, DiemChau; Truong, Daniel D.

doi:10.1016/0014-2999(94)00743-q

Cited by 14 publications

(2 citation statements)

References 33 publications

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“…In a model of traumatic injury, ACEA-1021, giving 30 min (15 mg/kg iv bolus followed by 10 mg/kg/h infusion) after the induction of SDH, was reported to reduce hemispheric ischemic damage (39% reduction in infarct size) [52]. ACEA-1021 also was found to attenuate myoclonus in cardiac arrest rats [53]. In a rat MCAO model of transient focal ischemia, ip administration of ACEA-1021 was reported to reduce cerebral infarct volumes and incidence of hemiparesis [20].…”

Section: Potential Therapeutic Applicationsmentioning

confidence: 97%

Glycine/NMDA Receptor Antagonists as Potential CNS Therapeutic Agents: ACEA-1021 and Related Compounds

Cai¹

2006

CTMC

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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.

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Section: Potential Therapeutic Applicationsmentioning

confidence: 97%

Glycine/NMDA Receptor Antagonists as Potential CNS Therapeutic Agents: ACEA-1021 and Related Compounds

Cai¹

2006

CTMC

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“…ACEA-1021 R = R = Me 6 7 ACEA-1328 R = Me, R = Cl In vivo ACEA 1021 reduced the rate of propagation of cortical spreading depression (39), an effect consistent with blockade of NMDA receptors. ACEA 1021 also decreased audiogenic myoclonus in resuscitated rats following cardiac arrest (40), and the minimum alveolar concentration for halothane (42), effects which suggest a reduction of excitatory amino acid neurotransmission. Moreover, ACEA 1021 decreased in vivo [ 125 I]MK-801 binding in the penumbral zone beneath experimentally induced acute subdural hematoma, indicating that it reduces pathological activation of NMDA receptors in ischemic brain tissue (17).…”

Section: Pharmacologymentioning

confidence: 99%

ACEA 1021: Flip or Flop?

2004

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Inasmuch 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.

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Synthesis of a 11C-labelled nitrated 1,4-dihydroquinoxaline-2,3-dione, the NMDA glycine receptor antagonist ACEA 1021 (Licostinel)

Thorell

Stone‐Elander

Duelfer

et al. 1998

J Label Compd Radiopharm

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ACEA 1021 (6,7‐dichloro‐5‐nitro‐1,4‐dihydroquinoxaline‐2,3‐dione, Licostinel) is a potent antagonist for the glycine site of the NMDA receptor. With the purpose of evaluating the drug's biodistribution in vivo as well as its potential as a PET tracer for the glycine binding sites, ACEA 1021 was labelled in the heterocyclic ring with carbon‐11 in a five‐step synthesis. The radiolabelling precursor, derived from [11C]cyanide, was diethyl [1‐11C]oxalate. Yields of its cyclization with the deactivated nitrated diamine, 4,5‐dichloro‐3‐nitro‐1,2‐phenylenediamine, were too low to be reliable for the planned in vivo studies. Instead, diethyl [1‐11C]oxalate was reacted with 4,5‐dichloro‐1,2‐ phenylenediamine to give [2‐11C]6,7‐dichloro‐1,4‐dihydroquinoxaline‐2,3‐dione (DCQX). Interference from the excess diamine during the subsequent nitration reaction was reduced by two methods. After formation of [2‐11C]DCQX, unlabelled diethyl oxalate was added and allowed to cyclize before adding the nitrating agent, giving a carrier‐added product suitable for use in pharmacokinetic studies. For the non‐carrier‐added tracer studies, the diamine was condensed with acetic acid before adding fuming HNO3/concentrated H2SO4. Both procedures gave high conversions of [2‐11C]DCQX to [11C]ACEA 1021, which was subsequently isolated by semi‐preparative liquid chromatography. The total synthesis time was 70–80 min. The conversions according to radio‐analytical LC were 25–30% and isolated yields for the five‐step synthesis were≈5–10% (decay‐corrected, based on [11C]CN− at end of trapping). The specific activity of the no‐carrier‐added product was 15–20 GBq/μmol at end‐of‐synthesis. © 1998 John Wiley & Sons, Ltd.

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Strychnine-insensitive glycine site antagonists attenuate a cardiac arrest-induced movement disorder

Cited by 14 publications

References 33 publications

Glycine/NMDA Receptor Antagonists as Potential CNS Therapeutic Agents: ACEA-1021 and Related Compounds

Glycine/NMDA Receptor Antagonists as Potential CNS Therapeutic Agents: ACEA-1021 and Related Compounds

ACEA 1021: Flip or Flop?

Synthesis of a 11C-labelled nitrated 1,4-dihydroquinoxaline-2,3-dione, the NMDA glycine receptor antagonist ACEA 1021 (Licostinel)

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