(2R,4R)-APDC

EC50: 0.4 μM

2R,4R-APDC is a highly selective and relatively potent group II metabotropic glutamate receptor agonist for human mGlu2. L-Glutamate (Glu) is EAA neurotransmitter in the mammalian CNS. Its effects are mediated by a variety of presynaptic and postsynaptic neuronal receptors.

In vitro: 2R,4R-APDC blocked forskolin-stimulated cAMP with none of the other activities of lS,3R-ACPD. forskolin-stimulated cAMP formation in human mGluR2 expressing cells with about three-fold greater potency than lS,3R-ACPD were also inhibited by 2R,4R-APDC, which, unlike lS,3R-ACPD, exhibited no appreciable activation of phosphoinostide hydrolysis in human mGluR. Thus, 2R,4R-APDC should be a useful pharmacological tool to explore the functions of mGluRs coupled to inhibition of adenylate cyclase [1]. The effects of four isomers of APDC were investigated at glutamate receptors in vitro. (2R,4R)-APDC, an aza analog of the nonselective mGluR agonist (1S,3R)-ACPD possessed relatively high affinity for metabotropic glutamate receptors (mGluRs) with no effects on radioligand binding to NMDA, AMPA, or kainate receptors up to 100 íM. None of the other APDC isomers exhibited significant mGluR binding affinity, indicating that this interaction is highly stereospecific [2].

In vivo: Both (1S,3R)-ACPD and (2R,4R)-APDC were effectively attenuating forskolin-stimulated cAMP formation in the adult rat cerebral cortex; however, while (1S,3R)-ACPD was also effectively stimulating basal tritiated inositol monophosphate production of the neonatal rat cerebral cortex, (2R,4R)-APDC was not effectively stimulating phosphoinositide hydrolysis in this tissue preparation. An augmentation of AMPA-induced excitation was produced by microelectrophoretic application of either (1S,3R)-ACPD or (2R,4R)-APDC to intact rat spinal neurons [2].

Clinical trial: Clinical study has been conducted.

References:
[1] Schoepp DD, Johnson BG, Salhoff CR, Valli MJ, Desai MA, Burnett JP, Mayne NG, Monn JA.  Selective inhibition of forskolin-stimulated cyclic AMP formation in rat hippocampus by a novel mGluR agonist, 2R,4R-4-aminopyrrolidine-2,4- dicarboxylate. Neuropharmacology. 1995 Aug;34(8):843-50.
[2] Monn JA, Valli MJ, Johnson BG, Salhoff CR, Wright RA, Howe T, Bond A, Lodge D, Spangle LA, Paschal JW, Campbell JB, Griffey K, Tizzano JP, Schoepp DD.  Synthesis of the four isomers of 4-aminopyrrolidine-2,4-dicarboxylate: identification of a potent, highly selective, and systemically-active agonist for metabotropic glutamate receptors negatively coupled to adenylate cyclase. J Med Chem. 1996 Jul 19; 39 (15):2990-3000.

Effects of the group II mGlu receptor agonist 2R,4R-APDC on dentate gyrus cell proliferation in the adult rat brain after diffuse brain injury.[Pubmed:21535937]

Neurol Res. 2011 May;33(4):381-8.

OBJECTIVES: Diffuse brain injury (DBI) has been shown to increase the proliferation of granule cell precursors in the adult dentate gyrus (DG). However, the mechanism by which DBI-induced cell proliferation in the DG may enhance seizure susceptibility remains largely unknown. MATERIALS AND METHODS: Using bromodeoxyuridine (BrdU) immunohistochemistry, we examined the effects of group II metabotropic glutamate receptor (mGluR) agonist, 2R,4R-4-aminopyrrolidine-2,4-dicarboxylate (2R,4R-APDC), on cell proliferation in the DG after DBI. RESULTS: It has been found that 2R,4R-APDC significantly blocked DBI-induced increase in the number of BrdU-positive cells in the DG, especially in hilus. In addition, double-label immunofluorescence staining showed that treatment with APDC did not affect the differentiation of newborn cells into neurons or astrocytes. Taken together, our findings indicate that the activation of mGluR system may inhibit the DBI-induced cell proliferation in the DG, but not the differentiation of newborn cells. DISCUSSION: It is suggested that 2R,4R-APDC has potential neuroprotection via inhibiting the aberrant neurogenesis induced by DBI, which is an important pathological basis of seizure or other abnormalities following DBI.

2R,4R-APDC influence on hypoxia-induced impairment of learning and memory processes in passive avoidance test.[Pubmed:15591640]

Pol J Pharmacol. 2004 Sep-Oct;56(5):527-37.

We investigated the effects of 2R,4R-APDC, a selective group II metabotropic glutamate receptor (II mGluR) agonist, on certain behaviors in rats subjected and non-subjected to hypoxia. Short-term hypoxia was used as a model of experimentally induced amnesia. 2R,4R-APDC given intracerebroventricularly (icv) at doses of 1 mumol and 100 nmol decreased the number of crossings and rearings in the open field, impaired acquisition and consolidation but improved retrieval in the passive avoidance tests. It also shortened the time spent in open arms and prolonged the time spent in closed arms, reduced the number of open and closed arms entries in an elevated "plus" maze, which is a measure of anxiety. Four-minute hypoxia (2% O(2), 98% N(2)) retrieval of conditioned responses, and exhibited an anxiogenic effect in the elevated "plus" maze in rats, i.e. it reduced the time spent in open arms and the number of entries to closed and open arms. 2R,4R-APDC effect on locomotor and exploratory activity was not changed after hypoxia, i.e. we observed inhibition of motility. This agonist of II mGluRs used at both doses before hypoxia significantly improved acquisition and retrieval, and had dual effect on consolidation, viz. at a dose of 1 mumol, it impaired this process and at a dose of 100 nmol it improved it. In the elevated "plus" maze, rats pretreated with 2R,4R-APDC and then subjected to hypoxia shortened the time spent in open arms and prolonged the time spent in closed arms, reduced the time spent in open arms, i.e. the drug exhibited anxiogenic effect. We conclude, therefore, that 2R,4R-APDC itself impaired acquisition and consolidation, enhanced retrieval but in rats undergoing hypoxia, it improved acquisition, retrieval and when used at the dose of 100 nmol enhanced consolidation. 2R,4R-APDC had beneficial effect in hypoxia-induced memory impairment in passive avoidance test.

Inhibitory effect of group II mGluR agonist 2R, 4R-APDC on cell proliferation in dentate gyrus in rats with epileptic seizure.[Pubmed:26241549]

Eur Rev Med Pharmacol Sci. 2015 Aug;19(15):2922-7.

OBJECTIVE: Epileptic seizure can increase the cell proliferation in dentate gyrus in brain, but the mechanism remains unclear. MATERIALS AND METHODS: In this study, using systemic bromodeoxyuridine (BrdU) to label the dividing cells, the inhibitory effect of group II metabotropic glutamate receptor (mGluR) agonist 2R, 4R-4-aminopyrrolidine-2, 4-dicarboxylate (2R, 4R-APDC) on cell proliferation in dentate gyrus in rats after pilocarpine-induced status epilepticus (SE) was investigated. RESULTS: Results found that, 2R, 4R-APDC could significantly inhibit the behavioral seizure and block the seizure-induced increase of BrdU-positive cells in dentate gyrus, especially in hilus. Double-label immunofluorescence staining showed that, 2R, 4R-APDC did not affect the ability of newborn cells to differentiate into neurons or astrocytes. CONCLUSIONS: 2R, 4R-APDC not only has anticonvulsant effect on adult rats with pilocarpine-induced SE, but also has neuroprotective effect by reducing the abnormal regeneration of nerves.

2R, 4R-APDC decreases cell proliferation in the dentate gyrus of adult rats: the effect of 2R, 4R-APDC on cell proliferation.[Pubmed:17712274]

Neuroreport. 2007 Sep 17;18(14):1459-62.

This study investigated the effects of group II metabotropic glutamate receptor agonist, 2R, 4R-4-aminopyrrolidine-2,4-dicarboxylate (2R, 4R-APDC), on cell proliferation in the dentate gyrus of adult rats. 2R, 4R-APDC at a dose of 1 and 10 nmol/day resulted in decreased bromodeoxyuridine immunoreactive cells in the dentate gyrus. In addition, we found that APDC treatment had no effect on the number of BrdU+ and GFAP(+)-labeled cells or BrdU+ and NeuN(+)-labeled cells compared with controls. These data suggest that group II metabotropic glutamate receptor is an important site for glutamate's regulation on cell proliferation in the dentate gyrus, but 2R, 4R-APDC had no effects on newborn cell's ability to differentiate into neurons or astrocytes.

Pharmacological agents acting at subtypes of metabotropic glutamate receptors.[Pubmed:10530808]

Neuropharmacology. 1999 Oct;38(10):1431-76.

Metabotropic (G-protein-coupled) glutamate (mGlu) receptors have now emerged as a recognized, but still relatively new area of excitatory amino acid research. Current understanding of the roles and involvement of mGlu receptor subtypes in physiological/pathophysiological functions of the central nervous system has been recently propelled by the emergence of various structurally novel, potent, and mGlu receptor selective pharmacological agents. This article reviews the evolution of pharmacological agents that have been reported to target mGlu receptors, with a focus on the known receptor subtype selectivities of current agents.

Synthesis of the four isomers of 4-aminopyrrolidine-2,4-dicarboxylate: identification of a potent, highly selective, and systemically-active agonist for metabotropic glutamate receptors negatively coupled to adenylate cyclase.[Pubmed:8709133]

J Med Chem. 1996 Jul 19;39(15):2990-3000.

The four isomers of 4-aminopyrrolidine-2,4-dicarboxylate (APDC) were prepared and evaluated for their effects at glutamate receptors in vitro. (2R,4R)-APDC (2a), an aza analog of the nonselective mGluR agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate (1S,3R)-ACPD, 1), was found to possess relatively high affinity for metabotropic glutamate receptors (mGluRs) (ACPD-sensitive [3H]glutamate binding IC50 = 6.49 +/- 1.21 microM) with no effects on radioligand binding to NMDA, AMPA, or kainate receptors up to 100 microM. None of the other APDC isomers showed significant mGluR binding affinity, indicating that this interaction is highly stereospecific. Both 1 and 2a were effective in decreasing forskolin-stimulated cAMP formation in the adult rat cerebral cortex (EC50 = 8.17 +/- 2.21 microM for 1; EC50 = 14.51 +/- 5.54 microM for 2a); however, while 1 was also effective in stimulating basal tritiated inositol monophosphate production in the neonatal rat cerebral cortex (EC50 = 27.7 +/- 5.2 microM), 2a (up to 100 microM) was ineffective in stimulating phosphoinositide hydrolysis in this tissue preparation, further supporting our previous observations that 2a is a highly selective agonist for mGluRs negatively coupled to adenylate cyclase. Microelectrophoretic application of either 1 or 2a to intact rat spinal neurons produced an augmentation of AMPA-induced excitation (95 +/- 10% increase for 1, 52 +/- 6% increase for 2a). Intracerebral injection of 1 (400 nmol) produced characteristic limbic seizures in mice which are not mimicked by 2a (200-1600 nmol, ic). However, the limbic seizures induced by 1 were blocked by systemically administered 2a in a dose-dependent manner (EC50 = 271 mg/kg, ip). It is concluded that (2R,4R)-APDC (2a) is a highly selective, systemically-active agonist of mGluRs negatively coupled to adenylate cyclase and that selective activation of these receptors in vivo can result in anticonvulsant effects.

Selective inhibition of forskolin-stimulated cyclic AMP formation in rat hippocampus by a novel mGluR agonist, 2R,4R-4-aminopyrrolidine-2,4- dicarboxylate.[Pubmed:8532165]

Neuropharmacology. 1995 Aug;34(8):843-50.

Metabotropic glutamate receptors (mGluRs) are a heterogeneous family of G-protein coupled receptors that are linked to multiple second messengers in the rat hippocampus. The compound 1S,3R-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) has been widely used to activate this class of receptors and study their functions in situ. However, 1S,3R-ACPD acts on multiple mGluR subtypes to produce multiple alterations in second messengers. We report here that the aza-substituted analog of 1S,3R-ACPD, 2R,4R-4-aminopyrrolidine-2,4-dicarboxylate (2R,4R-APDC), is a highly selective agonist for negatively-coupled cAMP-linked mGluRs in the rat hippocampus, with similar potency in mGluR2 expressing cells. 1S,3R-ACPD decreases forskolin-stimulated cAMP formation, increases basal cAMP formation, and increases phosphoinositide hydrolysis in the rat hippocampus. However, 2R,4R-APDC inhibited forskolin-stimulated cAMP, but had none of the other activities of 1S,3R-ACPD. Furthermore, 2R,4R-APDC had no measurable ionotropic glutamate receptor affinity in rat hippocampus, as indicated by lack of effects on basal and glutamate agonist-evoked [3H]norepinephrine release. 2R,4R-APDC also inhibited forskolin-stimulated cAMP formation in human mGluR2 expressing cells with about three-fold greater potency than 1S,3R-ACPD, but unlike 1S,3R-ACPD, showed no appreciable activation of phosphoinostide hydrolysis in human mGluR1 alpha expressing cells. Thus, 2R,4R-APDC should be a useful pharmacological agent to explore the functions of mGluRs coupled to inhibition of adenylate cyclase.

(2R,4R)-APDC is a selective group II metabotropic glutamate receptors (mGluRs) agonist. (2R,4R)-APDC has anticonvulsant and neuroprotective effects.

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