Actions of D and L forms of 2-amino-5-phosphonovalerate and 2-amino-4-phosphonobutyrate in the cat spinal cord

Davies, J.; Watkins, Johnathan

doi:10.1016/0006-8993(82)91017-4

Cited by 292 publications

(128 citation statements)

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“…No qualitative differences were seen between APV and D-APV, although D-APV was slightly more effective than APV at high concentrations. Our observations are thus consistent with the suggestion that D-APV is the active component in APV (Stone et al, 198 1;Davies and Watkins, 1982). Both drugs were, as expected, reasonably selective antagonists of NMDA neuroexcitation on cortical neurons, but we found here that neither drug was absolutely selective at low millimolar concentrations.…”

Section: Discussionsupporting

confidence: 93%

“…2). The NMDA antagonist activity of APV, a racemate, resides predominantly in its D-isomer (D-APV); the L-isomer probably has only minimal NMDA antagonist activity (Stone et al, 198 1;Davies and Watkins, 1982). We therefore tested the ability of D-APV alone to antagonize GNT acutely, and we found a concentration+ffect relationship similar to that found with the racemate (perhaps slightly more effective at high concentrations, consistent with the inherent 2-fold increase in active isomer over the racemate) (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Pharmacology of glutamate neurotoxicity in cortical cell culture: attenuation by NMDA antagonists

1988

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The antagonist pharmacology of glutamate neurotoxicity was quantitatively examined in murine cortical cell cultures. Addition of 1- 3 mM DL-2-amino-5-phosphonovalerate (APV), or its active isomer D-APV, acutely to the exposure solution selectively blocked the neuroexcitation and neuronal cell selectively blocked the neuroexcitation and neuronal cell loss produced by N-methyl-D-aspartate (NMDA), with relatively little effect on that produced by either kainate or quisqualate. As expected, this selective NMDA receptor blockade only partially reduced the neuroexcitation or acute neuronal swelling produced by the broad-spectrum agonist glutamate; surprisingly, however, this blockade was sufficient to reduce glutamate- induced neuronal cell loss markedly. Lower concentrations of APV or D- APV had much less protective effect, suggesting that the blockade of a large number of NMDA receptors was required to acutely antagonize glutamate neurotoxicity. This requirement may be caused by the amplification of small amounts of acute glutamate-induced injury by subsequent release of endogenous NMDA agonists from injured neurons, as the “late” addition of 10–1000 microM APV or D-APV (after termination of glutamate exposure) also reduced resultant neuronal damage. If APV or D-APV were present both during and after glutamate exposure, a summation dose-protection relationship was obtained, showing substantial protective efficacy at low micromolar antagonist concentrations. Screening of several other excitatory amino acid antagonists confirmed that the ability to antagonize glutamate neurotoxicity might correlate with ability to block NMDA-induced neuroexcitation: The reported NMDA antagonists ketamine and DL-2-amino- 7-phosphono-heptanoate, as well as the broad-spectrum antagonist kynurenate, were all found to attenuate glutamate neurotoxicity substantially; whereas gamma-D-glutamylaminomethyl sulfonate and L- glutamate diethyl ester, compounds reported to block predominantly quisqualate or kainate receptors, did not affect glutamate neurotoxicity. The present study suggests that glutamate neurotoxicity may be predominantly mediated by the activation of the NMDA subclass of glutamate receptors--occurring both directly, during exposure to exogenous compound, and indirectly, due to the subsequent release of endogenous NMDA agonists. Given other studies linking NMDA receptors to channels with unusually high calcium permeability, this suggestion is consistent with previous data showing that glutamate neurotoxicity depends heavily on extracellular calcium.

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Section: Discussionsupporting

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Pharmacology of glutamate neurotoxicity in cortical cell culture: attenuation by NMDA antagonists

1988

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“…by Watkins & Evans, 1981;Foster & Fagg, 1984;Fagg, 1985), while a fourth sub-type has been proposed on the basis of the potent antagonist actions of L-2-amino-4-phosphonobutanoate (L-AP4, a glutamate analogue) at specific sub-populations of acidic amino acid-using synapses (Koerner & Cotman, 1981;Slaughter & Miller, 1981;Evans et al, 1982;Davies & Watkins, 1982;Collins, 1982;Lanthorn et al, 1984). The mechanism by which AP4 suppresses synaptic excitation, however, has not yet been elucidated (see Butcher et al 1983; Harris & Fagg, 1985).…”

mentioning

confidence: 99%

Cl⁻/Ca²⁺‐dependent L‐glutamate binding sites do not correspond to 2‐amino‐4‐phosphonobutanoate‐sensitive excitatory amino acid receptors

Fagg¹,

Lanthorn²

1985

British J Pharmacology

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1 A series of phosphono and phosphino analogues of glutamate were used to compare the pharmacological properties of (a) ClP/Ca2+-dependent, 2-amino-4-phosphonobutanoate (AP4)-sen- (IC50 values> 1001iM). Inactive compounds which exhibited activity in the binding assay did not reverse the synaptic depressant effects of AP4, indicating that they were neither agonists nor antagonists at AP4-sensitive synapses. 4 The lack of correspondence between (a) the Cl-/Ca2 -dependent, AP4-sensitive population of L-[3H]-glutamate binding sites and (b) AP4-sensitive synaptic responses indicates that these binding sites are not the receptors through which AP4 exerts its neuropharmacological effects. The possibility that Cl-/Ca2+-dependent 'binding sites' represent transport into resealed SPM vesicles is discussed. 5 Electrophysiological data demonstrate that AP4-sensitive synaptic receptors display a high degree of ligand selectivity. High antagonist potency is shown only by glutamate analogues with unmodified a-amino and a-carboxyl groups, and with a bifunctional (dianionic) o-terminal.

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“…The initial inhibitory effect is consistent with the other electrophysiological studies and may be mediated through several mechanisms. The most likely mechanism may be that of presynaptic blockade of excitatory amino acid release, a mechanism that has been demonstrated for L-AP4 in several recent studies (Davies and Watkins, 1982;Gannon et al, 1989;Forsythe and Clements, 1990). One possible problem with this hypothesis is that a higher concentration of L-PSer was needed in the CAI area of the hippocampus than in other areas (Table 3).…”

Section: Molecular and Chemical Neuropathologymentioning

confidence: 96%

“…The best case for a presynaptic location, however, has been made for the AN receptor. Davies and Watkins (1982) have shown that L-AP4 has little direct effect on NMDA, Glu, KA, or QA excitation of dorsal horn neurons, but potently depresses synaptically evoked excitation, believed to be mediated by Glu. This implies presynaptic antagonism of neurotransmitter release.…”

Section: Pharmacological Similarity Of L-pser and Lap4mentioning

confidence: 99%

Possible roles ofl-phosphoserine in the pathogenesis of Alzheimer’s disease

Klunk

McClure

Pettegrew

1991

Molecular and Chemical Neuropathology

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L-PhOSphoseflne is a membrane metabolite that is elevated in Alzheimer's disease brain. This compound has close structural similarity to L-glutamate. Electrophysiological studies indicate that L-phosphoserme has an acute inhibitory effect, but a delayed excitatory action. A hypothesis is developed based on pharmacological and electrophysiological studies that suggest that the inhibition may be mediated through presyrtaptic inhibition of L-glutamate release or perhaps antagonism of postsynaptic kainic acid receptors. The mechanism of the delayed excitation may lie in the tendency of L-phosphoserine to mimic the action of L-2-amino-4-phosphOnobutyric acid, a blocker of chloride-and calcium-sensitive L-glutamate transport. L-PhosphOserine has also been found to be a competitive antagonist at the N-methyl-o-aspartate recognition site and an antagonist of metabotropic receptor-mediated hydrolysis of inositol phospholipids. Because of these actions, there are several potentially important implications for the elevation of L-phosphoserme in Alzheimer's disease, including production memory impairment through presyn-

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Actions of D and L forms of 2-amino-5-phosphonovalerate and 2-amino-4-phosphonobutyrate in the cat spinal cord

Cited by 292 publications

References 14 publications

Pharmacology of glutamate neurotoxicity in cortical cell culture: attenuation by NMDA antagonists

Pharmacology of glutamate neurotoxicity in cortical cell culture: attenuation by NMDA antagonists

Cl⁻/Ca²⁺‐dependent L‐glutamate binding sites do not correspond to 2‐amino‐4‐phosphonobutanoate‐sensitive excitatory amino acid receptors

Possible roles ofl-phosphoserine in the pathogenesis of Alzheimer’s disease

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Actions of D and L forms of 2-amino-5-phosphonovalerate and 2-amino-4-phosphonobutyrate in the cat spinal cord

Cited by 292 publications

References 14 publications

Pharmacology of glutamate neurotoxicity in cortical cell culture: attenuation by NMDA antagonists

Pharmacology of glutamate neurotoxicity in cortical cell culture: attenuation by NMDA antagonists

Cl−/Ca2+‐dependent L‐glutamate binding sites do not correspond to 2‐amino‐4‐phosphonobutanoate‐sensitive excitatory amino acid receptors

Possible roles ofl-phosphoserine in the pathogenesis of Alzheimer’s disease

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Cl⁻/Ca²⁺‐dependent L‐glutamate binding sites do not correspond to 2‐amino‐4‐phosphonobutanoate‐sensitive excitatory amino acid receptors