L-AP4

L-Cysteine and L-AP4 microinjections in the rat caudal ventrolateral medulla decrease arterial blood pressure.[Pubmed:25450419]

Auton Neurosci. 2014 Dec;186:45-53.

The thiol amino acid L-cysteine increases arterial blood pressure (ABP) when injected into the cerebrospinal fluid space in conscious rats, indicating a pressor response to centrally acting L-cysteine. A prior synaptic membrane binding assay suggests that L-cysteine has a strong affinity for the L-2-amino-4-phosphonobutyric acid (L-AP4) binding site. The central action of L-cysteine may be viaL-AP4 sensitive receptors. The present study investigated cardiovascular responses to L-cysteine and L-AP4 microinjected into the autonomic area of the caudal ventrolateral medulla (CVLM) where inhibitory neurons regulate ABP via pre-sympathetic vasomotor neurons. Both the injection of L-cysteine and L-AP4 in the CVLM sites identified with L-glutamate produced the same depressor and bradycardic responses in urethane-anesthetized rats. Neither a prior antagonist microinjection of MK801 for the N-methyl-D-aspartate (NMDA) receptor nor CNQX for the non-NMDA receptor attenuated the responses to L-cysteine, but the combination of the two receptor blocking with an additional prior injection abolished the response. In contrast, either receptor blockade alone abolished the response to L-AP4, indicating distinct mechanisms between responses to L-cysteine and L-AP4 in the CVLM. The results indicate that the CVLM is a central active site for L-cysteine's cardiovascular response. Central L-cysteine's action could be independent of the L-AP4 sensitive receptors. Cardiovascular regulation may involve endogenous L-cysteine in the CVLM. Further multidisciplinary examinations are required to elaborate on L-cysteine's functional roles in the CVLM.

Behavioral comparison of sucrose and l-2-amino-4-phosphonobutyrate (L-AP4) tastes in rats: does L-AP4 have a sweet taste?[Pubmed:18598739]

Neuroscience. 2008 Aug 13;155(2):522-9.

Even though it is generally thought that umami stimuli such as monosodium glutamate (MSG) and sweet stimuli such as sucrose are detected by different taste receptors, these stimuli appear to share taste qualities when amiloride (a sodium channel blocker) is present to reduce the sodium taste. Single fiber recording studies of the facial and glossopharyngeal nerves have shown that encoding of L-2-amino-4-phosphonobutyrate (L-AP4), a potent mGluR4 agonist that elicits a taste quite similar to MSG, may occur in the same fibers that also encode sweet stimuli. This suggests that L-AP4 and sweet substances may activate common receptors or afferent signaling mechanisms. We report results of behavioral experiments that test this hypothesis. In the first study, rats conditioned to avoid sucrose or L-AP4 generalized the aversion to the opposite substance, indicating that both substances elicited similar tastes. However, two taste discrimination experiments showed that rats easily discriminated between sucrose and L-AP4 over a wide range of concentrations, even when the cue function of sodium associated with L-AP4 was reduced by amiloride and neutralized by adding equimolar concentrations of NaCl to sucrose. These data suggest that even though L-AP4 and sucrose elicit similar taste qualities, one or both substances also elicit other taste qualities not shared by the opposite substance. They also suggest that the taste-mGluR4 receptor and the signal pathway activated by L-AP4 are not the same as those activated by sucrose. These data, when combined with fiber recording data, suggest that there is convergence of L-AP4 and sucrose signals at some point early in the gustatory pathway.

Diastereoselective synthesis of 2-amino-4-phosphonobutanoic acids by electrophilic substitution and tin-Peterson olefination of bis-lactim ethers derived from cyclo-[L-AP4-D-Val].[Pubmed:16930050]

J Org Chem. 2006 Sep 1;71(18):6958-74.

Electrophilic substitutions on lithiated Schollkopf's bis-lactim ethers derived from cyclo-[L-AP4-D-Val] take place regio- and stereoselectively at the alpha-position of the phosphonate ester. Subsequent olefination of alpha-silyl-, alpha-phosphoryl-, and alpha-stannyl-stabilized phosphonate carbanions give rise exclusively to vinylphosphonates. Both processes allow a direct and stereoselective access to a variety of 4-substituted and 3,4-disubstituted 2-amino-4-phosphonobutanoic acids (AP4 derivatives) in enantiomerically pure form that may be useful tools for characterizing the molecular pharmacology of metabotropic glutamate receptors (mGluRs) of group III. The relative stereochemistry was assigned from X-ray diffraction analyses or NMR studies of 1,2-oxaphosphorinane and other cyclic derivatives. In accordance to density functional theory (DFT) calculations, the syn-selectivity in the electrophilic substitutions may originate from the intervention of seven- and eight-membered chelate structures in which the bis-lactim ether moiety shields one of the faces of the phosphonate carbanion. DFT calculations for the tin-Peterson olefination of alpha-stannyl stabilized phosphonate carbanions indicate that rate and selectivity are determined in the initial carbon-carbon bond formation step where the unlike transition structures leading to (Z)-vinylphosphonates are favored both in the gas phase and in THF solution.

Evidence that L-AP5 and D,L-AP4 can preferentially block cone signals in the rat retina.[Pubmed:17430605]

Vis Neurosci. 2007 Jan-Feb;24(1):9-15.

Several lines of evidence suggest that, as concentrations of two agonists of group III metabotropic glutamate receptors are increased, cone contributions to the b-wave are blocked before rod contributions. Application of L-AP5 (L-2-amino-5-phosphonobutyric acid) at concentrations of 50 microM and D,L-AP4 (D,L-2-amino-4-phosphonobutyric acid) at concentrations 2 microM had a greater effect in reducing the amplitude of the rat ERG b-wave at high light intensities than at low light intensities. The amplitude reduction occurs at flash intensities that saturate rod photoreceptor responses. When steady backgrounds are used to saturate rod photoreceptors, the b-wave responses show increased long-wavelength sensitivity. Responses on a rod saturating background are blocked by adding L-AP5 or AP4 at the above concentrations to the perfusate. Further evidence for metabotrophic receptors being involved comes from the observation that even when ionotropic glutamate receptors are pharmacologically blocked with MK801 and DNQX, AP4 selectively blocks cone contributions to the b-wave. Thus we suggest that the type III metabotrophic receptors on depolarizing cone bipolar cells or cone synaptic terminals are affected by concentrations of L-AP5 and D,L-AP4 that have minimal effects on rod bipolar cells or rod synaptic terminals.

Antagonism of the synaptic depressant actions of L-AP4 in the lateral perforant path by MAP4.[Pubmed:7617150]

Neuropharmacology. 1995 Feb;34(2):239-41.

A new mGluR antagonist, MAP4 (the alpha-methyl derivative of L-AP4), was found to antagonize the synaptic depressant actions of L-AP4 at the lateral perforant path synapse, in rat hippocampal slices.

The agonist selectivity of a class III metabotropic glutamate receptor, human mGluR4a, is determined by the N-terminal extracellular domain.[Pubmed:8742431]

Neuroreport. 1995 Dec 29;7(1):117-20.

To test the hypothesis that the determinants for agonist selectivity of class III metabotropic glutamate receptors (mGluRs) are localized in the N-terminal extracellular domain, a chimaeric cDNA was constructed where 519 amino acids of the N-terminal extracellular domain of human mGluR1b were exchanged with the corresponding region of human mGluR4. The pharmacological profile of the chimaera, designated hmGlu(R4)1-519/1b, was analysed by recordings of intracellular calcium concentration ([Ca2+]i) in transiently transfected HEK 293 cells and compared with that of human mGluR1b and human mGluR4a stably expressed in Chinese hamster ovary cells. Application of 100 microM L-2-amino-4-phosphonobutyrate (L-AP4), a class III mGluR-specific agonist, induced a rise in [Ca2+]i in hmGlu(R4)1-519/1b but not in hmGluR1b expressing cells. In contrast, application of quisqualate (100 microM) induced a rise in [Ca2+]i at hmGluR1b but not at hmGlu(R4)1-519/1b. Dose-response analysis with L-AP4 and L-glutamate at hmGlu(R4)1-519/1b revealed a half-maximal effect (EC50) of 16.0 microM and 196 microM, respectively. The EC50 values for quisqualate, glutamate and (1S,3R)-ACPD at hmGluR1b were 10.25 microM, 225 microM and 3060 microM, respectively. The rank order of agonist potency of hmGlu(R4)1-519/1b corresponds to that of hmGluR4 (L-AP4 > L-glutamate > (1S,3R)-ACPD > quisqualate) but is different from that of hmGluR1b (quisqualate > glutamate >> (1S,3R)-ACPD).

Molecular diversity of glutamate receptors and implications for brain function.[Pubmed:1329206]

Science. 1992 Oct 23;258(5082):597-603.

The glutamate receptors mediate excitatory neurotransmission in the brain and are important in memory acquisition, learning, and some neurodegenerative disorders. This receptor family is classified in three groups: the N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)-kainate, and metabotropic receptors. Recent molecular studies have shown that many receptor subtypes exist in all three groups of the receptors and exhibit heterogeneity in function and expression patterns. This article reviews the molecular and functional diversity of the glutamate receptors and discusses their implications for integrative brain function.

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.

L-APB is a potent and specific agonist for the group III mGluRs, with EC50s of 0.13, 0.29, 1.0, 249 μM for mGlu4, mGlu8, mGlu6 and mGlu7 receptors, respectively.

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