dizocilpine-maleate and 6-chloro-2-(1-piperazinyl)pyrazine

Prepulse inhibition (PPI) is disrupted in many neuropsychiatric diseases. Molecules such as 5-HT

Topics: Aminopyridines; Animals; Brain; Dizocilpine Maleate; Hippocampus; Indoles; Mice; Prefrontal Cortex; Prepulse Inhibition; Pyrazines; Receptor, Serotonin, 5-HT2C; Receptors, N-Methyl-D-Aspartate

N-methyl-D-aspartate receptors are one member of a family of ionotropic glutamate receptors that play a pivotal role in synaptic plasticity processes associated with learning and have become attractive therapeutic targets for diseases such as depression, anxiety, schizophrenia, and neuropathic pain. NYX-2925 ((2S, 3R)-3-hydroxy-2-((R)-5-isobutyryl-1-oxo-2,5-diazaspiro[3.4]octan-2-yl)butanamide) is one member of a spiro-β-lactam-based chemical platform that mimics some of the dipyrrolidine structural features of rapastinel (formerly GLYX-13: threonine-proline-proline-threonine) and is distinct from known N-methyl-D-aspartate receptor agonists or antagonists such as D-cycloserine, ketamine, MK-801, kynurenic acid, or ifenprodil.. The in vitro and in vivo pharmacological properties of NYX-2925 were examined.. NYX-2925 has a low potential for "off-target" activity, as it did not exhibit any significant affinity for a large panel of neuroactive receptors, including hERG receptors. NYX-2925 increased MK-801 binding to human N-methyl-D-aspartate receptor NR2A-D subtypes expressed in HEK cells and enhanced N-methyl-D-aspartate receptor current and long-term potentiation (LTP) in rat hippocampal slices (100-500 nM). Single dose ex vivo studies showed increased metaplasticity in a hippocampal LTP paradigm and structural plasticity 24 hours after administration (1 mg/kg p.o.). Significant learning enhancement in both novel object recognition and positive emotional learning paradigms were observed (0.01-1 mg/kg p.o.), and these effects were blocked by the N-methyl-D-aspartate receptor antagonist CPP. NYX-2925 does not show any addictive or sedative/ataxic side effects and has a therapeutic index of >1000. NYX-2925 (1 mg/kg p.o.) has a cerebrospinal fluid half-life of 1.2 hours with a Cmax of 44 nM at 1 hour.. NYX-2925, like rapastinel, activates an NMDA receptor-mediated synaptic plasticity process and may have therapeutic potential for a variety of NMDA receptor-mediated central nervous system disorders.

Topics: Animals; Dendritic Spines; Dizocilpine Maleate; Dose-Response Relationship, Drug; Emotions; Excitatory Amino Acid Agents; HEK293 Cells; Hippocampus; Humans; Learning; Male; Memory; Molecular Structure; Neuronal Plasticity; Oligopeptides; Pyramidal Cells; Pyrazines; Rats; Receptors, N-Methyl-D-Aspartate

The behavioural effect of dopamine D1-like receptor agonists (SKF 38393, SKF 81297) and a D2-like receptor agonist (quinpirole), administered alone and in combination, was tested in rats pretreated with a single injection of an NMDA antagonist (MK-801, CPP) or vehicle. Agonist-induced behaviour was monitored by automated activity meters and direct observation using a checklist scoring method. Pretreatment with MK-801 (0.05 mg/kg, SC, 30 min) had no significant effect (compared to controls) on the behavioural response to SKF 38393 (7.5 mg/kg SC), SKF 81297 (0.2 mg/kg SC) or quinpirole (0.1 and 0.25 mg/kg SC) administered alone. In contrast, MK-801 markedly increased locomotion (activity counts and scores) induced by co-administration of a D1-like plus a D2-like agonist [SKF 38393 (7.5 mg/kg) plus quinpirole (0.25 mg/kg), SKF 81297 (0.2 mg/kg) plus quinpirole (0.1 mg/kg)]. The behavioural response to the non-selective dopamine agonist apomorphine (0.5 mg/kg SC) was also enhanced by MK-801. Pretreatment with CPP (0.1 mg/kg SC, 30 min) also significantly increased the locomotor response to co-administration of SKF 38393 plus quinpirole administered alone, but had no effect on the behavioural response to separate injection of these agonists. MK-801 (0.05 mg/kg SC, 30 min) also enhanced the behavioural response to bilateral injection into the nucleus accumbens of SKF 38393 plus quinpirole (1.0 plus 0.4 microgram/side, respectively). These data suggest that in the intact rat, the enhancement of dopamine-mediated behaviour by either MK-801 or CPP requires concomitant stimulation of D1-like and D2-like receptors, possible located within the nucleus accumbens. The effect of these NMDA antagonists on dopamine function is similar to that of repeated electroconvulsive shock (ECS), indicating that one of the actions of ECS may be to reduce NMDA receptor function.

Topics: Animals; Dizocilpine Maleate; Dopamine Agonists; Electroshock; Excitatory Amino Acid Antagonists; Injections, Intraventricular; Male; Motor Activity; Nucleus Accumbens; Pyrazines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate