Disease relevance of Licostinel

• BACKGROUND AND PURPOSE: Licostinel (ACEA 1021; 5-nitro-6, 7-dichloro-2,3-quinoxalinedione), a competitive antagonist of glycine at the N-methyl-D-aspartate (NMDA) receptor, is an effective neuroprotective agent in animal models of cerebral ischemia [1].
• CONCLUSIONS: A short infusion of licostinel in doses up to 3.0 mg/kg is safe and tolerable in acute stroke patients [1].
• Both ACEA-1021 and ACEA-1031 reduced cerebral infarct volumes and were associated with a reduced incidence of hemiparesis resulting from MCA occlusion [2].
• In rats receiving ACEA-1021 only, minimal hemodynamic depression and moderate hypoventilation were observed [3].
• ACEA 1021 combined with (S)-MDMA also prevented (S)-MDMA-induced hyperthermia without causing hypothermia or preventing an (S)-MDMA-induced increase in locomotor activity [4].

Psychiatry related information on Licostinel

• In the present study the effects of ACEA 1021 (5, 7.5, 8, 10, 15 and 20 mg/kg i.p.) on sniffing stereotypy, locomotor activity, prepulse inhibition of the acoustic startle response, the anti-cataleptic properties and spatial learning were tested [5].

High impact information on Licostinel

• Licostinel may be a safer and better tolerated neuroprotective agent than many of the previously evaluated NMDA antagonists [1].
• The purpose of this study was to assess the safety, tolerability, and pharmacokinetics of licostinel in patients with acute stroke [1].
• For example, using fixed agonist concentrations (10 microM glycine and 100 microM glutamate) IC50 values for ACEA-1021 with four binary combinations were as follows: NMDA receptor (NR)1A/2A, 29 nM; NR1A/2B, 300 nM; NR1A/2C, 120 nM; NR1A/2D, 1500 nM [6].
• Apparent dissociation constants (Kb values) for ACEA-1021 and ACEA-1031 ranged between 6 and 8 nM for oocyte assays and between 5 and 7 nM for neuronal assays [6].
• Our results suggest that these additional effects of ACEA 1021 may contribute to its anticonvulsive properties in mice as well as to its neuroprotective properties in animal models of cerebral ischemia [7].

Chemical compound and disease context of Licostinel

• The neuroprotective activity of ACEA 1021 (5-nitro-6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione; licostinel), a selective antagonist at the strychnine-insensitive glycine site associated with the NMDA receptor complex, has been investigated in various models of focal cerebral ischemia [8].
• Of these, memantine, ACEA-1021 and, to the lesser degree, eliprodil attenuated expression of cocaine-conditioned motor activity at doses that did not significantly affect spontaneous motor activity [9].

Biological context of Licostinel

• The neuroprotective effect of 5-nitro-6,7-dichloro-2,3-quinoxalinedione (ACEA 1021), a selective NMDA receptor antagonist with nanomolar affinity for the glycine binding site, was examined in rat cortical mixed neuronal/glial cultures [10].
• Structure-activity relationship studies indicate that a cyano group is a good replacement for the nitro group in the 5-position of licostinel while 5-carboxy, 5-ester, 5-ketone and 5-amide derivatives showed reduced potency [11].
• 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 [12].

Anatomical context of Licostinel

• Rats were administered either vehicle (n = 7), ACEA 1021 (n = 7) or dizocilpine (n = 5) and then underwent 90 min middle cerebral artery occlusion [13].

Associations of Licostinel with other chemical compounds

• Our results suggest that the in vivo neuro-protective actions of ACEA-1021 and ACEA-1031 are predominantly due to inhibition at NMDA receptor glycine sites, although additional inhibition at non-NMDA receptors may play an ancillary role [6].
• The glycine-site modulators, (+)-HA-966, ACEA 1021 and milacemide, and the polyamine/NR2B-selective antagonist, eliprodil, also failed to substitute fully for NPC 17742 in rats and monkeys [14].

Analytical, diagnostic and therapeutic context of Licostinel

• During MCAO and the first 24 h of reperfusion, rats (n = 10) were administered e55-nitro-6,7-dichloro-2,3-quinoxalinedione (ACEA 1021) i.v. as a bolus infusion of 5 mg/kg followed by 3.5 mg/kg/h (Low-Dose) or 10 mg/kg followed by 7 mg/kg/ h (High-Dose) for 24 h [15].
• The bolus dose of ACEA-1021 was followed by a continuous intravenous infusion of vehicle or ACEA-1021 at 14 mg.kg-1.h-1 [3].

References