N-Hydroxypyrrolidon-(2), ein neuer Pyrrolidonderivat-Typ

Smrt, J.; Beránek, Jaroslav; Horák, M.

doi:10.1135/cccc19591672

Cited by 22 publications

(9 citation statements)

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“…Racemic HA-966 was synthesized by the method of Smrt et al (17). The individual enantiomers (R)-(+)-HA-966 and (S)-(-)-HA-966 were prepared from Dand L-methionine, respectively, as described (18).…”

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confidence: 99%

“…Similarly, the (-)-enantiomer appears to be responsible for the effects on striatal dopamine content. Interestingly, the structurally related compounds y-hydroxybutyrate and y-butyrolactone also induce sedation and inhibit dopamine release from striatal neurones (17,23,24). The accumulation of dopamine and the sedative effects induced by (-)-HA-966 are thus probably due to a selective interruption of the flow of nerve impulses in the dopaminergic nigrostriatal tract.…”

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confidence: 99%

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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.

Singh¹,

Donald²,

Foster³

et al. 1990

Proc. Natl. Acad. Sci. U.S.A.

109

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confidence: 99%

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confidence: 99%

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.

Singh¹,

Donald²,

Foster³

et al. 1990

Proc. Natl. Acad. Sci. U.S.A.

109

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“…Racemic HA-966 was prepared by the method of Smrt et al (1954). The enantiomers of HA-966 were prepared [as described by Chapdelaine and Warwick (unpublished observations)] from the respective isomers of N-tert-butoxycarbonylmethionine (Bachem, Philadelphia, PA, U.S.A.).…”

Section: Methodsmentioning

confidence: 99%

Stereoselectivity for the (R)‐Enantiomer of HA‐966 (l‐Hydroxy‐3‐Aminopyrrolidone‐2) at the Glycine Site of the N‐Methyl‐d‐Aspartate Receptor Complex

Pullan

Britt

Chapdelaine

et al. 1990

Journal of Neurochemistry

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HA-966 (1-hydroxy-3-aminopyrrolidone-2) is an antagonist at the glycine allosteric site of the N-methyl-D-aspartate receptor ionophore complex. Unlike presently known glycine antagonists, HA-966 is chiral. We report stereoselectivity for the (R)-enantiomer at the glycine antagonist site. In [3H]glycine binding, the (R)-enantiomer has an IC50 of 4.1 +/- 0.6 microM. The racemic mixture has an IC50 of 11.2 +/- 0.5 microM, whereas (S)-HA-966 has an IC50 greater than 900 microM. In glycine-stimulated [3H]1-[1-(2- thienyl)cyclohexyl]piperidine binding, the (R)-enantiomer inhibits with an IC50 of 121 +/- 61 microM, whereas the racemic mixture has an IC50 of 216 +/- 113 microM and (S)-HA-966 is inactive. The inhibition by (R)-HA-966 can be prevented by the addition of glycine. (R)-HA-966 and racemic HA-966, but not (S)-HA-966, also prevent N-methyl-D-aspartate cytotoxicity in cortical cultures. The (R)-enantiomer and, less potently, the (S)-enantiomer inhibit N-methyl-D-aspartate-evoked [3H]norepinephrine release from rat hippocampal slices (IC50 values of about 0.3 mM and 1.6 mM, respectively), but only the inhibition by (R)-HA-966 is reversed by added glycine. In glutamate-evoked contractions of the guinea pig ileum, (R)-HA-966 causes a glycine-reversible inhibition (IC50 of about 150 microM), whereas (S)-HA-966 is much less potent (IC50 of greater than 1 mM). These results demonstrate stereoselectivity of the glycine antagonist site of the N-methyl-D-aspartate receptor complex in a variety of tissues and assays. The stereoselectivity also confirms the specificity of N-methyl-D-aspartate receptors in glutamate-evoked contractions of the guinea pig ileum, and supports their similarity to central N-methyl-D-aspartate receptors.

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“…The D-a-aminoadipic acid was prepared by the resolution of the DL-form using D-lysine as a resolving agent. The drug HA966 was synthesised by the method of Smrt et al, 1959. Compounds were checked for their purity by both mass and nuclear magnetic resonance spectroscopy and were found to be greater than 99% pure.…”

Section: Methodsmentioning

confidence: 99%

Is Glutamate a Trigger Factor in Epileptic Hyperactivity?

et al. 1981

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The effects of glutamate and aspartate antagonists were studied on limb-jerk frequency and EEG patterns in rats made epileptic by cobalt implantation in the sensorimotor cerebral cortex. The results of this study were as follows: (1) alpha-Amino-4-phosphonobutyric acid (0.055--1.10 mM) decreased or completely prevented the epileptic manifestations. The effect was reversible 30 min after washing with artificial CSF solution. (2) DL-Pyroglutamic acid completely abolished the myoclonic jerks and EEG spikes. (3) alpha-Amino-5-phosphonovaleric acid and alpha-D-amino-adipic acid significantly reduced the frequency of epileptic spikes and myoclonic jerks. (4) Other analogs, alpha-amino-3-phosphonopropionic acid (0.6 mM), alpha-amino phosphonocaproic acid (0.95), and hydroxy-3-amino pyrrolidone-2 were without effect. (5) Glutamate itself did not decrease the epileptic manifestations.

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N-Hydroxypyrrolidon-(2), ein neuer Pyrrolidonderivat-Typ

Cited by 22 publications

References 0 publications

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.

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.

Stereoselectivity for the (R)‐Enantiomer of HA‐966 (l‐Hydroxy‐3‐Aminopyrrolidone‐2) at the Glycine Site of the N‐Methyl‐d‐Aspartate Receptor Complex

Is Glutamate a Trigger Factor in Epileptic Hyperactivity?

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