Disease relevance of HA 966

• In contrast, none of the glycine partial agonists or antagonists, namely (+/-)HA-966, D-cycloserine, MDL-29,951, DPCQ, MNQX or L-701 252 were able to prevent the L-CPA-induced loss in body weight, L-CPA-induced granule cell necrosis and behavioral disturbances when administered to rats [1].
• However, HA-966 did not attenuate QA-mediated brain injury [2].
• The neuroprotective effects of (R)-HA-966 and (S)-HA-966 (3-amino-1-hydroxy-2-pyrrolidinone) were examined in an MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced animal model of Parkinson's disease [3].

Psychiatry related information on HA 966

• The results showed that MK-801 was more potent than (+)HA-966 in producing anterograde amnesia and impairing expression, while (-)HA-966 did not produce anterograde amnesia [4].
• When given intravenously to mice, racemic HA-966 and the (S)-enantiomer prevented tonic extensor seizures from low-intensity electroshock (ED50 = 13.2 and 8.8 mg/kg, respectively) [5].
• Administration of HA-966 (0.1-10 mg/kg, i.m.) 30 min before testing impaired DNMS performance dose-dependently, starting at doses of 3.2 mg/kg; the memory deficity following the highest dose (10 mg/kg) was associated with prolonged response latencies [6].
• None of the NMDA antagonists had any effect on the cerebellar neurochemistry when injected alone or had any effect on animal behavior except for dizocilpine, CPP, CGP40116 and (+/-)HA-966 which resulted in a transient sedation for between three and five hours immediately following their administration [1].

High impact information on HA 966

• Enantiomers of HA-966 (3-amino-1-hydroxypyrrolid-2-one) exhibit distinct central nervous system effects: (+)-HA-966 is a selective glycine/N-methyl-D-aspartate receptor antagonist, but (-)-HA-966 is a potent gamma-butyrolactone-like sedative [7].
• In radioligand binding experiments, HA-966 inhibited strychnine-insensitive 3H-glycine binding to rat cerebral cortex synaptic plasma membranes with an IC50 of 17.5 microM [8].
• Moreover, Cl-KYN can also completely inhibit the binding of [3H]glutamate to the primary transmitter recognition site for the NMDA receptor, whereas HA-966 only partially reduces this binding [9].
• In this work we show that, in synaptic membranes prepared from rat brain, Cl-KYN and HA-966 inhibit the binding of [3H]glycine [9].
• In contrast, HA-966 increases [3H]CPP binding, affecting the affinity but not the maximal number of binding sites [9].

Chemical compound and disease context of HA 966

• Administration of CG 3703 (500 micrograms/animal i.v.) in combination with HA 966 (100 mg/kg body weight i.p.) at 20.00 h prevented the decrease in DA levels and the rise in plasma PRL values [10].

Biological context of HA 966

• Anticonvulsant agents, dizocilpine maleate, enadoline and HA 966 have different effects on N-methyl-DL-aspartate-induced immediate early gene induction in mice [11].
• Only antagonists to the CNS strychnine-sensitive glycine receptor (strychnine, brucine), and not antagonists to the glycine modulatory site of the NMDA receptor (DCQX, 7-CKA, HA-966) or the GABAA receptor (bicuculline methiodide, picrotoxin), prevented mitochondrial inhibitor (antimycin A)-induced RPT cell death [12].
• 2. 7-Clkyn and HA-966 produced a selective depression of the polysynaptic reflex (PSR) while negligibly affecting the activity of the monosynaptic reflex (MSR) [13].

Anatomical context of HA 966

• Other rats were injected with saline or R(+) HA-966 (10 microg/side), intra-medial prefrontal cortex, on the expression day [14].
• OBJECTIVE: This study investigates the putative anxiolytic, R(+) HA-966, applied locally at the level of the mesocorticolimbic dopamine cell bodies in the ventral tegmental area (VTA), on the acquisition and expression of conditioned fear [14].
• A similar retention deficit with HA-966 infusions in the temporal cortex or lateral entorhinal cortex was seen when testing took place 23 days later, whereas a markedly weaker effect was observed when the retention period was reduced to 3 days [15].
• Mg2+-like selective antagonism of excitatory amino acid-induced responses by alpha, epsilon-diaminopimelic acid, D-alpha-aminoadipate and HA-966 in isolated spinal cord of frog and immature rat [16].
• In addition HA 966 shows regional differences in its interaction with the strychnine-insensitive glycine receptor, being about six times more potent on striatal than on hippocampal synaptosomes, suggesting a possible heterogeneity of glycine sites recognized by HA 966 or different intrinsic activity in the two brain regions [17].

Associations of HA 966 with other chemical compounds

• The binding of [3H] (+)-5-methyl-10,11-dihydro-5H-dibenzocyclohepten-5,10-imine maleate (MK-801), used as an index of NMDA receptor activation, is completely inhibited by Cl-KYN but only partially by HA-966 [9].
• The drugs tested were: NBQX and GYKI-52466, selective AMPA receptor antagonists, ketamine, MK-801, R(+) HA-966 and ACEA-0762, selective NMDA receptor antagonists, and ACEA-1031, ACEA-1328 and ACEA-0593, NMDA receptor antagonists that also show inhibition of non-NMDA receptors [18].
• The anterograde amnestic effects of non-competitive NMDA antagonists MK-801 and HA-966 on classic fear conditioning in goldfish (Carassius auratus) were examined in a series of experiments [4].
• When administered together at submaximal doses, HA-966 and BHT 920 produced an additive effect in the induction of adrenal tyrosine hydroxylase [19].
• Locomotion evoked with 5 mg/kg N-n-propyl-N-phenylethyl-p (3-hydroxyphenyl) ethylamine hydrochloride (RU 24213; D2 receptor agonist) was attenuated by HA 966 and MK 801, but not by CPP, CGP 40116 (except at higher doses) or NBQX [20].

Gene context of HA 966

• Thus, the TRH analogue and HA 966 counteracted each other regarding the DAergic system, which again illustrates the stimulatory effect of the TRH analogue on the release of DA from TIDA neurons [10].
• After intraventricular administration (5 micrograms/rat) in normal animals, HA-966 produced significant induction of tyrosine hydroxylase [19].
• HA 966 also had a relatively slow onset of action as compared to PCP [21].
• Uncompetitive and competitive NMDA antagonists were examined in generalization studies, as were the racemate and the (+) and (-) stereoisomers of HA 966 (3-amino-1-hydroxypyrrolid-2-one) [21].
• Acute injection of the NMDA receptor antagonists CGP 40116 (5 mg/kg) and HA 966 (5 mg/kg), and to a lesser extent eliprodil (10 mg/kg), greatly elevated DDC in both structures, whilst having no effect on (nigra) or inhibiting (striatum) 5-HTPDC [22].

Analytical, diagnostic and therapeutic context of HA 966

• In another experiment microinjections of 7-Cl-KY (8 nmol) and HA-966 (100 nmol) into the DPAG raised the threshold of aversive electrical stimulation of the rat DPAG [23].
• The objective of the present study was to examine whether microinjections of the functional NMDA receptor antagonist, 3-amino-1-hydroxy-2-pyrrolidinone ((+)-HA-966), might result in effects mimicking those seen in lesion studies [15].
• FK960 [N-(4-acetyl-1-piperazinyl)-p-fluorobenzamide monohydrate], a novel potential antidementia drug, restores the regional cerebral blood flow response abolished by scopolamine but not by HA-966: a positron emission tomography study with unanesthetized rhesus monkeys [24].
• The zinc chelator, ethylenediaminetetra acetic acid (EDTA) (300mg/kg), and the NMDA receptor antagonist, HA-966 (60mg/kg), both disrupted the theta rhythm, but did not antagonize soman-induced seizures, neither separately, nor in combination [25].

References