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Chemical Compound Review

CHEMBL351464     3-amino-1-hydroxy-pyrrolidin- 2-one

Synonyms: SureCN253915, HA-966, AG-G-77750, AG-K-62199, ANW-56672, ...
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Disease relevance of HA 966


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


  1. Failure of glycine site NMDA receptor antagonists to protect against L-2-chloropropionic acid-induced neurotoxicity highlights the uniqueness of cerebellar NMDA receptors. Widdowson, P.S., Gyte, A.J., Upton, R., Wyatt, I. Brain Res. (1996) [Pubmed]
  2. HA-966 (1-hydroxy-3-aminopyrrolidone-2) selectively reduces N-methyl-D-aspartate (NMDA)-mediated brain damage. McDonald, J.W., Uckele, J., Silverstein, F.S., Johnston, M.V. Neurosci. Lett. (1989) [Pubmed]
  3. Neuroprotective effects of the strychnine-insensitive glycine site NMDA antagonist (R)-HA-966 in an experimental model of Parkinson's disease. Kanthasamy, A.G., Kanthasamy, A., Matsumoto, R.R., Vu, T.Q., Truong, D.D. Brain Res. (1997) [Pubmed]
  4. Comparative anterograde amnestic and anticonvulsant effects of two types of NMDA receptor antagonists: MK-801 and HA-966. Xu, X., Klinger, P., Davis, R. Psychopharmacology (Berl.) (1995) [Pubmed]
  5. Different stereoselectivity of the enantiomers of HA-966 (3-amino-1-hydroxy-2-pyrrolidinone) for neuroprotective and anticonvulsant actions in vivo. Vartanian, M.G., Taylor, C.P. Neurosci. Lett. (1991) [Pubmed]
  6. The glycine/NMDA receptor antagonist HA-966 impairs visual recognition memory in rhesus monkeys. Matsuoka, N., Aigner, T.G. Brain Res. (1996) [Pubmed]
  7. 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. Singh, L., Donald, A.E., Foster, A.C., Hutson, P.H., Iversen, L.L., Iversen, S.D., Kemp, J.A., Leeson, P.D., Marshall, G.R., Oles, R.J. Proc. Natl. Acad. Sci. U.S.A. (1990) [Pubmed]
  8. HA-966 antagonizes N-methyl-D-aspartate receptors through a selective interaction with the glycine modulatory site. Foster, A.C., Kemp, J.A. J. Neurosci. (1989) [Pubmed]
  9. Different modes of action of 3-amino-1-hydroxy-2-pyrrolidone (HA-966) and 7-chlorokynurenic acid in the modulation of N-methyl-D-aspartate-sensitive glutamate receptors. Danysz, W., Fadda, E., Wroblewski, J.T., Costa, E. Mol. Pharmacol. (1989) [Pubmed]
  10. Semicircadian rhythm of dopamine release in the mediobasal hypothalamus in awake rats during pseudopregnancy: evidence that a thyrotropin-releasing hormone analogue stimulates dopamine release and thereby inhibits prolactin secretion. Timmerman, W., Poelman, R.T., Westerink, B.H., Schuiling, G.A. Neuroendocrinology (1995) [Pubmed]
  11. Anticonvulsant agents, dizocilpine maleate, enadoline and HA 966 have different effects on N-methyl-DL-aspartate-induced immediate early gene induction in mice. Woodburn, V.L., Oles, R., Poat, J., Woodruff, G.N., Hughes, J. Neuroscience (1993) [Pubmed]
  12. A putative cytoprotective receptor in the kidney: relation to the neuronal strychnine-sensitive glycine receptor. Miller, G.W., Schnellmann, R.G. Life Sci. (1994) [Pubmed]
  13. Selective depression of the spinal polysynaptic reflex by the NMDA receptor antagonists in an isolated spinal cord in vitro. Maruoka, Y., Ohno, Y., Tanaka, H., Yasuda, H., Ohtani, K., Sakamoto, H., Kawabe, A., Tamamura, C., Nakamura, M. Gen. Pharmacol. (1997) [Pubmed]
  14. Biochemical and behavioral anxiolytic-like effects of R(+)HA-966 at the level of the ventral tegmental area in rats. Morrow, B.A., Elsworth, J.D., Zito, C., Roth, R.H. Psychopharmacology (Berl.) (1999) [Pubmed]
  15. Interference with visual memory in rats following infusion of the functional NMDA receptor antagonist, HA-966, into temporal regions. Myhrer, T., Andersen, J.M. Eur. J. Pharmacol. (2001) [Pubmed]
  16. 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. Evans, R.H., Francis, A.A., Watkins, J.C. Brain Res. (1978) [Pubmed]
  17. GV 150526A, 7-Cl-kynurenic acid and HA 966 antagonize the glycine enhancement of N-methyl-D-aspartate-induced [3H]noradrenaline and [3H]dopamine release. Mennini, T., Mancini, L., Reggiani, A., Trist, D. Eur. J. Pharmacol. (1997) [Pubmed]
  18. Antinociceptive effects of NMDA and non-NMDA receptor antagonists in the tail flick test in mice. Lutfy, K., Cai, S.X., Woodward, R.M., Weber, E. Pain (1997) [Pubmed]
  19. Central regulation of adrenal tyrosine hydroxylase: interaction between dopamine and GABA systems. Gabor, R., Regunathan, S., Sourkes, T.L. Neuropharmacology (1989) [Pubmed]
  20. Facilitation of dopamine D1 receptor- but not dopamine D1/D2 receptor-dependent locomotion by glutamate antagonists in the reserpine-treated mouse. Starr, M.S., Starr, B.S. Eur. J. Pharmacol. (1993) [Pubmed]
  21. Competitive and uncompetitive N-methyl-D-aspartate antagonist discriminations in pigeons: CGS 19755 and phencyclidine. Baron, S.P., Woods, J.H. Psychopharmacology (Berl.) (1995) [Pubmed]
  22. Opposite effects of glutamate antagonists and antiparkinsonian drugs on the activities of DOPA decarboxylase and 5-HTP decarboxylase in the rat brain. Fisher, A., Starr, M.S. Brain Res. (2000) [Pubmed]
  23. Anxiolytic effect of glycine antagonists microinjected into the dorsal periaqueductal grey. Matheus, M.G., Nogueira, R.L., Carobrez, A.P., Graeff, F.G., Guimarães, F.S. Psychopharmacology (Berl.) (1994) [Pubmed]
  24. 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. Tsukada, H., Yamazaki, S., Noda, A., Inoue, T., Matsuoka, N., Kakiuchi, T., Nishiyama, S., Nishimura, S. Brain Res. (1999) [Pubmed]
  25. Pharmacological agents, hippocampal EEG, and anticonvulsant effects on soman-induced seizures in rats. Myhrer, T., Skymoen, L.R., Aas, P. Neurotoxicology (2003) [Pubmed]
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