D-AP4

Physiological role of group III metabotropic glutamate receptors in visually responsive neurons of the rat superficial superior colliculus.[Pubmed:10762314]

Eur J Neurosci. 2000 Mar;12(3):847-55.

There is evidence from immunohistochemical and in situ hybridization studies for the presence of Group I, II and III metabotropic glutamate receptors (mGluRs) in the rat superficial superior colliculus (SSC). The purpose of this study was to investigate if manipulation of Group III mGluRs affects visual responses in the SSC. Drugs were applied by iontophoresis and single neuron activity was recorded extracellularly. L-AP4 (Group III agonist) resulted in a reduction of visual responses in most neurons, but also a potentiation in others. The effect of L-AP4 is drug- and stereospecific in that application of D-AP4 did not significantly affect visual responses. L-AP4 application also resulted in a potentiation of the response to iontophoretically applied NMDA. The effects of MPPG and CPPG (Group III antagonists) were compared with the effect of L-AP4 in the same neuron and were found to produce the opposite effect to L-AP4. Furthermore, the effect of L-AP4 could be blocked by coapplication of MPPG or CPPG. Presynaptic depression of glutamate release is a possible mechanism by which L-AP4 could reduce visual responses in the SSC whereas the potentiation of visual responses by L-AP4 could be due to a reduction of GABAergic inhibition. The finding that MPPG and CPPG, as well as antagonizing the L-AP4 effect, have a direct effect on visual responses suggests that Group III mGluRs are activated by endogenous transmitter released during visual stimulation.

Inhibition of AMPA receptor-stimulated 57Co2+ influx by D- and L-2-amino-4-phosphonobutanoic acid (D- and L-AP4) and L-serine-O-phosphate (L-SOP) in cultured cerebellar granule cells.[Pubmed:9175612]

Neuropharmacology. 1997 Mar;36(3):335-43.

This study describes the inhibition of 57Co2+ influx through Ca2+-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, consequent to the application of L-2-amino-4-phosphonobutanoic acid (L-AP4), D-AP4 and L-serine-O-phosphate (L-SOP) in cultured cerebellar granule cells. The forskolin-stimulated accumulation of cyclic AMP was inhibited by (2S,1'S,2'S)-2-(carboxycyclopropyl)glycine (L-CCG-1) with an IC50 = 491 +/- 135 nM and by L-AP4 in a biphasic manner (IC50(1) = 232 +/- 61 nM and IC50(2) = >300 microM), confirming the presence of group II and group III mGlu receptors, respectively. 57Co2+ influx was stimulated by kainate (EC50 = 42.2 +/- 11.3 microM) and, in the presence of 30 microM cyclothiazide, by (S)-5-fluorowillardiine (EC50 = 0.7 +/- 0.1 microM) and (S)-AMPA (EC50 = 2.8 +/- 0.5 microM). The effects of the latter were abolished by 10 microM 6-nitro-7-sulphamoylbenzo[f]quinoxaline-2,3-dione (NBQX). L-AP4 (IC50 = >300 microM), D-AP4 (IC50 = >100 microM) and L-SOP (IC50 = 199 +/- 6 microM) inhibited 6 microM (S)-AMPA-stimulated 57Co2+ influx, whereas L-CCG-1 (up to 10 microM), 300 microM (RS)-3,5-dihydroxyphenylglycine, 300 microM (+/-)-baclofen and 1 mM carbachol were ineffective. Pre-incubation with either pertussis toxin (250 ng/ml, 48 hr), 1 mM dibutyryl cyclic AMP, or the potent group III mGlu receptor antagonist (RS)-alpha-cyclopropyl-4-phosphonophenylglycine ((RS)-CPPG), tested at 400 microM, failed to alter the inhibition of AMPA receptor activity by 300 microM L-SOP. Unlike 10 microM NBQX, neither L-AP4, D-AP4 or L-SOP (tested at 1 mM) inhibited the binding of 10 nM (S)-[3H]5-fluorowillardiine (a selective AMPA receptor ligand) to granule cell membranes. Therefore, in these neurones, high concentrations (>100 microM) of L-AP4, L-SOP and D-AP4 inhibit Ca2+-permeable AMPA receptors by a mechanism distinct from known mGlu receptor action and at a site independent from that for AMPA receptor agonists.

Inhibitors of metabotropic glutamate receptors produce amnestic effects in chicks.[Pubmed:8080954]

Neuroreport. 1994 May 9;5(9):1037-40.

Two antagonists of metabotropic glutamate receptors, L-AP4 and MCPG, were tested in a one-trial passive avoidance task in the chick to investigate whether these receptor subtypes play a role in learning and memory. Drugs were injected i.c. L-AP4 produced amnestic effects when injected pre- or post-training. When injected pretraining, amnesia onset was observed after 1 h post-training. D-AP4 had no effect on memory formation. MCPG in comparison had no effect when injected post-training. When injected pretraining, the onset of amnesia was dose-dependent, ranging from 2 to 1 h post-training. When injecting MCPG along with the mGluR agonist ACPD, no amnestic effect was visible. ACPD on its own had no effect at the dose used.

Comparison of excitatory amino acid-stimulated phosphoinositide hydrolysis and N-[3H]acetylaspartylglutamate binding in rat brain: selective inhibition of phosphoinositide hydrolysis by 2-amino-3-phosphonopropionate.[Pubmed:2542463]

J Neurochem. 1989 Jul;53(1):273-8.

The activation of phosphoinositide hydrolysis by ibotenate (IBO) in brain slices and the binding of N-[3H]acetylaspartyl-L-glutamate (NAAG) to brain membranes are biochemical parameters previously shown to be selectively inhibited by 2-amino-4-phosphonobutyrate (AP4). We have examined whether the binding of [3H]NAAG and stimulation of phosphoinositide hydrolysis by IBO are indexing the same or different populations of AP4-sensitive excitatory amino acid sites in brain. L-AP4 and D,L-2-amino-3-phosphonopropionate (D,L-AP3) were found to be about equipotent inhibitors of IBO-stimulated phosphoinositide hydrolysis. L-AP4 and D,L-AP3 did not inhibit stimulation of phosphoinositide hydrolysis by the cholinoceptor agonist carbachol. The L-isomers of serine-O-phosphate and alpha-aminoadipate were selective inhibitors of IBO-stimulated phosphoinositide hydrolysis, but were less potent than L-AP4 or D,L-AP3. When these compounds were examined for their ability to inhibit [3H]NAAG binding to membranes of rat forebrain, the relative order of potency was L-alpha-aminoadipate = D-alpha-aminoadipate greater than L-AP4 greater than L-serine-O-phosphate greater than D-AP4 much greater than D,L-AP3. Concentrations of NAAG up to 10(-2) M did not stimulate phosphoinositide hydrolysis. Thus, although both assays are sensitive to L-AP4 inhibition, they appear to represent disparate excitatory amino acid sites in brain. Furthermore, D,L-AP3 appears to be a more selective inhibitor of excitatory amino acid-stimulated phosphoinositide hydrolysis than L-AP4, and might be a more useful pharmacological tool to define the function of these receptor sites in brain.

Excitatory amino acid agonist-antagonist interactions at 2-amino-4-phosphonobutyric acid-sensitive quisqualate receptors coupled to phosphoinositide hydrolysis in slices of rat hippocampus.[Pubmed:2834517]

J Neurochem. 1988 May;50(5):1605-13.

Studies were carried out to define the relative affinities and intrinsic activities of excitatory amino acid agonists that activate receptor sites coupled to phosphoinositide hydrolysis in brain. Slices of rat hippocampus were prelabeled with myo-[3H]inositol, and agonist stimulation was indexed by measuring the accumulation of [3H]inositol monophosphate [( 3H]IP) in the presence of Li+. It was observed that ibotenic (IBO) and quisqualic (QUIS) acids both elicit highly significant, concentration-dependent stimulation of phosphoinositide hydrolysis. Whereas maximal stimulation by IBO (10(-3) M) was four- to fivefold over basal values, the maximal effect of QUIS (10(-4) M) was less (about twofold). Based on the relative concentrations required for 50% maximal stimulation, QUIS was 20 times more potent than IBO. Stimulation of phosphoinositide hydrolysis by either IBO or QUIS was additive to the effects of nonexcitatory amino acid agonists (carbachol and norepinephrine) in this tissue. However, the stimulatory effects of IBO plus QUIS were not additive. At greater than or equal to 10(-4) M, QUIS significantly inhibited phosphoinositide hydrolysis by a maximal stimulatory concentration of IBO (10(-3) M) to a level observed with QUIS alone. Other excitatory amino acid agonists, including kainate, N-methyl-D-aspartate, and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), had no stimulatory effects at concentrations as high as 10(-3) M. The D,L or L forms of 2-amino-4-phosphonobutyric acid (AP4), but not D-AP4, significantly enhanced [3H]IP levels to approximately 135% of basal values.(ABSTRACT TRUNCATED AT 250 WORDS)

Utilization of the resolved L-isomer of 2-amino-6-phosphonohexanoic acid (L-AP6) as a selective agonist for a quisqualate-sensitized site in hippocampal CA1 pyramidal neurons.[Pubmed:7953634]

Brain Res. 1994 Jun 27;649(1-2):203-7.

Brief exposure of rat hippocampal slices to quisqualic acid (QUIS) sensitizes neurons to depolarization by the alpha-amino-omega-phosphonate excitatory amino acid (EAA) analogues AP4, AP5 and AP6. These phosphonates interact with a novel QUIS-sensitized site. Whereas L-AP4 and D-AP5 cross-react with other EAA receptors, DL-AP6 has been shown to be relatively selective for the QUIS-sensitized site. This specificity of DL-AP6, in conjunction with the apparent preference of this site for L-isomers, suggested that the hitherto unavailable L-isomer of AP6 would be a potent and specific agonist. We report the resolution of the D- and L-enantiomers of AP6 by fractional crystallization of the L-lysine salt of DL-AP6. We also report the pharmacological responses of kainate/AMPA, NMDA, lateral perforant path L-AP4 receptors and the CA1 QUIS-sensitized site to D- and L-AP6, and compare these responses to the D- and L-isomers of AP3, AP4, AP5 and AP7. The D-isomers of AP4, AP5 and AP6 were 5-, 3- and 14-fold less potent for the QUIS-sensitized site than their respective L-isomers. While L-AP4 and L-AP5 cross-reacted with NMDA and L-AP4 receptors, L-AP6 was found to be highly potent and specific for the QUIS-sensitized site (IC50 = 40 microM). Its IC50 values for kainate/AMPA, NMDA and L-AP4 receptors were > 10, 3 and 0.8 mM, respectively. As with AP4 and AP5, sensitization to L-AP6 was reversed by L-alpha-aminoadipate.

The effects of a series of omega-phosphonic alpha-carboxylic amino acids on electrically evoked and excitant amino acid-induced responses in isolated spinal cord preparations.[Pubmed:7042024]

Br J Pharmacol. 1982 Jan;75(1):65-75.

1 The depressant actions on evoked electrical activity and the excitant amino acid antagonist properties of a range of omega-phosphonic alpha-carboxylic amino acids have been investigated in the isolated spinal cord preparations of the frog or immature rat. 2 When tested on dorsal root-evoked ventral root potentials, members of the homologous series from 2- amino-5-phosphonovaleric acid to 2-amino-8-phosphonooctanoic acid showed depressant actions which correlated with the ability of the substances to antagonize selectivity motoneuronal depolarizations induced by N-methyl-D-aspartate. 3 2-Amino-5-phosphonovalerate was the most potent substance of the series giving an apparent KD of 1.4 microM for the antagonism of responses to N-methyl-D-aspartate. 4 A comparison of the (+)- and (-)-forms of 2-amino-5-phosphonovalerate indicated that the N-methyl-D-aspartate antagonist activity and the neuronal depressant action of this substance were both due mainly to the (-)-isomer. 5 The (-)- and (+)-forms of 2-amino-4-phosphonobutyrate had different actions. The (-)-forms of this substance had a relatively weak and non-selective antagonist action on depolarizations induced by N-methyl-D-aspartate, quisqualate and kainate and a similarly weak depressant effect when tested on evoked electrical activity. The (+)-form was more potent than he (-)-form in depressing electrically evoked activity but did not antagonize responses to amino acid excitants. At concentrations higher than those required to depress electrically evoked activity, the (+)-form produced depolarization. This action was blocked by 2-amino-5-phosphonovalerate.