cis-ACPD

Predictive study by molecular modeling to promote specific probes of glutamate receptors, using methylated cyclic glutamic acid derivatives (trans- and cis-ACPD). Comparison with specific agonists.[Pubmed:9722425]

J Chem Inf Comput Sci. 1998 Jul-Aug;38(4):742-60.

Two classes of glutamate receptors (metabotropic and ionotropic) and their subclasses (groups I-III and N-methyl-D-aspartic acid (NMDA), kainic acid (KA)), respectively, are characterized by the binding of a L-glutamate moiety in a specific conformation. The conformations may be grouped by the two backbone torsion angles, chi1 [alpha-CO2-C(2)-C(3)-C4)] and chi2 [+NC(2)-C(3)-C(4)-gamma-CO2] and by the two characteristic distances between the potentially active functional groups, alpha-N+-gamma-CO2 (d1) and alpha-CO2-gamma-CO2 (d2). The conformational preferences of 2,3,4-methyl(a and b)-cis and trans-1-aminocyclopentane-1,3-dicarboxylate are discussed in the light of the physical features known for specific metabotropic (groups I-II) and specific ionotropic (NMDA, KA) agonists, respectively. The spatial orientation of the perceived functional groups was elucidated in cyclic derivatives which contain an embedded L-glutamate moiety in a particularly restricted conformation (relative to the C(2)-C(3)-C(4) bond) using a combination of NMR experimental results and mechanics and dynamics calculations. One important conclusion of the study is that a single glutamate receptor is privileged for each theoretical model considered by molecular dynamics. This study showed clearly what would be conformational preferences of cyclic glutamate derivatives following the geometrical isomerism of the methyl group.

Synthesis and pharmacology of 3-hydroxy-delta2-isoxazoline-cyclopentane analogues of glutamic acid.[Pubmed:12484537]

Farmaco. 2002 Nov;57(11):889-95.

The synthesis and pharmacology of two potential glutamic acid receptor ligands are described. Preparation of the bicyclic 3-hydroxy-delta2-isoxazoline-cyclopentane derivatives (+/-)-7 and (+/-)-8 was accomplished via 1,3-dipolar cycloaddition of bromonitrile oxide to suitably protected 1-amino-cyclopent-3-enecarboxylic acids. Their structure was established using a combination of 1H NMR spectroscopy and molecular mechanics calculations carried out on the intermediate cycloadducts (+/-)-11 and (+/-)-12. Amino acid derivatives (+/-)-7 and (+/-)-8 were assayed at ionotropic and metabotropic glutamic acid receptor subtypes and their activity compared with that of trans-ACPD and cis-ACPD. The results show that the replacement of the omega-carboxylic group of the model compounds with the 3-hydroxy-delta2-isoxazoline moiety abolishes or reduces drastically the activity at the metabotropic glutamate receptors. Conversely, on passing from cis-ACPD to derivative (+/-)-8, the agonist activity at NMDA receptors is almost unaffected.

In vitro and in vivo pharmacology of trans- and cis-(+-)-1-amino-1,3-cyclopentanedicarboxylic acid: dissociation of metabotropic and ionotropic excitatory amino acid receptor effects.[Pubmed:1849553]

J Neurochem. 1991 May;56(5):1789-96.

This study explored further the function of the metabotropic excitatory amino acid receptor in the rat brain. The trans and cis isomers of (+-)-1-amino-1,3-cyclopentane-dicarboxylic acid (ACPD) were characterized for relative affinities at ionotropic and metabotropic excitatory amino acid receptors in vitro, as well as ability to produce in vivo excitatory or excitotoxic effects in rats. trans-ACPD was about 12 times more potent in vitro as an agonist for metabotropic excitatory amino acid receptors when compared to its ability to displace N-methyl-D-aspartate (NMDA) ([3H]CGS-19755) receptor binding, cis-ACPD was about 30 times more potent as a displacer of [3H]CGS-19755 binding than as a stimulant of phosphoinositide hydrolysis. When administered intraperitoneally to neonatal rats, both cis- and trans-ACPD produced convulsions that were prevented by the competitive NMDA receptor antagonists, LY233053 and LY274614. cis-ACPD was six times more potent as a convulsant when compared to trans-ACPD. Both compounds were examined for excitotoxic effects in vivo following stereotaxic injection into the mature or neonatal rat striatum. Doses of trans-ACPD of up to 5,000 or 1,200 nmol produced few signs of striatal neuronal degeneration in the mature or neonatal brain, respectively. However, cis-ACPD produced extensive dose-related neuronal degeneration at doses of 100-1,000 nmol in the mature brain and 50-200 nmol in the neonatal brain. These studies suggest that, unlike the ionotropic excitatory amino acid receptors, activation of the metabotropic excitatory amino acid receptor does not result directly in excitatory effects, such as excitotoxicity.