cis-ACBD

Presynaptic excitability as a potential target for the treatment of the traumatic cerebellum.[Pubmed:15240995]

Pharmacology. 2004 Aug;71(4):192-8.

Using an extracellular recording method, we have previously shown a hyperexcitability of the presynaptic response in fluid percussion injury (FPI) in rats. In this study, we demonstrated that treatment with cis-ACBD, a glutamate reuptake inhibitor, depressed the presynaptic potential (PSP) in naive/sham controls, while it potentiated the PSP in FPI rats. On the contrary, (RS)-APICA, a selective group II metabotropic glutamate receptor antagonist, potentiated PSP in controls, but depressed PSP in FPI rats. These results indicate that an alteration of the normal function of metabotropic glutamate receptors and glutamate reuptake system or an altered reactivity of presynaptic fibers was induced by FPI. This alteration may contribute to the reported loss of Purkinje cells after FPI. PSP may be used as a potential tool for evaluating treatments of FPI or as a potential target for the prevention of Purkinje cell death.

L-trans-pyrrolidine-2,4-dicarboxylate and cis-1-aminocyclobutane-1,3-dicarboxylate behave as transportable, competitive inhibitors of the high-affinity glutamate transporters.[Pubmed:7905733]

Biochem Pharmacol. 1994 Jan 20;47(2):267-74.

The ability of two conformationally restricted analogues of L-glutamate to function as non-transportable inhibitors of plasma membrane L-glutamate transport was investigated in primary cultures of cerebellar granule cells and cortical astrocytes. L-trans-Pyrrolidine-2,4-dicarboxylic acid (L-trans-PDC) and cis-1-aminocyclobutane-1,3-dicarboxylic acid (cis-ACBD) behaved as linear competitive inhibitors of the uptake of D-[3H]aspartate (used as a non-metabolizable analogue of L-glutamate) exhibiting Ki values between 40 and 145 microM; L-trans-PDC being the more potent inhibitor in each preparation. However, both L-trans-PDC and cis-ACBD, over a concentration range of 1 microM-5 mM, dose-dependently stimulated the release of exogenously supplied D-[3H]aspartate from granule cells maintained in a continuous superfusion system. The stimulated release was independent of extracellular calcium ions; essentially superimposable dose-response profiles being obtained in the absence and presence of 1.3 mM CaCl2 and yielding EC50 values of 16-25 microM and 180-220 microM for L-trans-PDC and cis-ACBD, respectively. Stimulated release of D-[3H]aspartate was unaffected by either 300 microM D-(-)-2-amino-5-phosphonopentanoic acid [D-APV; a selective antagonist of the N-methyl-D-aspartate (NMDA) receptor] or by 25 microM 6-cyano-7-nitroquinoxaline-2,3-dione [CNQX; a selective antagonist of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor]. The release of D-[3H]-aspartate following stimulation by either L-trans-PDC or cis-ACBD was however markedly attenuated following substitution in the superfusion medium of sodium ions by choline ions. Taken together, these results support an action of L-trans-PDC and cis-ACBD consistent with that of being competitive substrates rather than non-transportable blockers of the plasma membrane L-glutamate uptake system.

Differentiation of substrate and nonsubstrate inhibitors of the high-affinity, sodium-dependent glutamate transporters.[Pubmed:10570036]

Mol Pharmacol. 1999 Dec;56(6):1095-104.

Within the mammalian central nervous system, the efficient removal of L-glutamate from the extracellular space by excitatory amino acid transporters (EAATs) has been postulated to contribute to signal termination, the recycling of transmitter, and the maintenance of L-glutamate at concentrations below those that are excitotoxic. The development of potent and selective inhibitors of the EAATs has contributed greatly to the understanding of the functional roles of these transporters. In the present study, we use a library of conformationally constrained glutamate analogs to address two key issues: the differentiation of substrates from nontransportable inhibitors and the comparison of the pharmacological profile of synaptosomal uptake with those of the individual EAAT clones. We demonstrate that the process of transporter-mediated heteroexchange can be exploited in synaptosomes to rapidly distinguish transportable from nontransportable inhibitors. Using this approach, we demonstrate that 2,4-methanopyrrolidine-2,4-dicarboxylate, cis-1-aminocyclobutane-1,3-dicarboxylate, and L-trans-2, 4-pyrrolidine dicarboxylate act as substrates for the rat forebrain synaptosomal glutamate uptake system. In contrast, L-anti-endo-3, 4-methanopyrrolidine-3,4-dicarboxylate, L-trans-2,3-pyrrolidine dicarboxylate, and dihydrokainate proved to be competitive inhibitors of D-[(3)H]aspartate uptake that exhibited little or no activity as substrates. When these same compounds were characterized for substrate activity by recording currents in voltage-clamped Xenopus laevis oocytes expressing the human transporter clones EAAT1, EAAT2, or EAAT3, it was found that the pharmacological profile of the synaptosomal system exhibited the greatest similarity with the EAAT2 subtype, a transporter believed to be expressed primarily on glial cells.

Inhibition of high affinity L-glutamic acid uptake into rat cortical synaptosomes by the conformationally restricted analogue of glutamic acid, cis-1-aminocyclobutane-1,3-dicarboxylic acid.[Pubmed:1673544]

Neurosci Lett. 1991 Jan 2;121(1-2):133-5.

The action of two cyclobutane derivatives of L-glutamic acid on the high affinity uptake of L-glutamic acid was investigated using a preparation of synaptosomes from rat cerebral cortex. cis-1-Aminocyclobutane-1,3-dicarboxylic acid (also known as trans-2,4-methanoglutamic acid) potently inhibited L-glutamic acid uptake (IC50 30 microM), whereas trans-1-aminocyclobutane-1,3-dicarboxylic acid (also known as cis-2,4-methanoglutamic acid), a potent N-methyl-D-aspartate (NMDA) agonist, was inactive. Analysis of the kinetics of L-glutamic acid uptake in the presence and absence of cis-1-aminocyclobutane-1,3-dicarboxylic acid (CACB) suggests that it may act as a competitive inhibitor (Ki 8 microM). CACB may be substrate for the L-glutamic acid high-affinity uptake carrier since preincubation of CACB with the synaptosomal preparation increased its potency in inhibiting L-glutamic acid uptake. The conformationally restricted structure of CACB may be indicative of the conformations of L-glutamic acid that interact with the high affinity uptake carrier.

Synthesis and activity of a potent N-methyl-D-aspartic acid agonist, trans-1-aminocyclobutane-1,3-dicarboxylic acid, and related phosphonic and carboxylic acids.[Pubmed:2145435]

J Med Chem. 1990 Oct;33(10):2905-15.

We report the synthesis of a series of 3-carboxy-, 3-(carboxymethyl)-, 3-(omega-phosphonoalkyl)-1-aminocyclobutane-1-carboxylic acids for evaluation as agonists or antagonists of neurotransmission at excitatory amino acid receptors, particularly N-methyl-D-aspartic acid (NMDA) receptors. The compounds were evaluated as agonists on their ability to depolarize the rat brain cortical wedge preparation or as antagonist of the actions of the selective agonists NMDA, quisqualic acid, and kainic acid. The chain-elongated glutamate derivatives with potential antagonist activity proved to be weak and frequently nonselective antagonists in this assay. The most noteworthy result was that trans isomer 7b was a very potent agonist, approximately 20 times more active than NMDA at NMDA receptors, while the cis isomer was 1/3 as potent as NMDA.