Synthesis of conformationally constrained glutamic acid homologues and investigation of their pharmacological profiles.
ABSTRACT Homologation of the glutamic acid chain together with conformational constraint is a commonly used strategy to achieve selectivity towards different types of glutamate receptors. We investigated the effects of a further increase in the distance between the amino acid moiety and the distal carboxylate group of model compounds (+/-)-1 and (+/-)-2 on their activity/selectivity profiles. We therefore synthesized new derivatives (+/-)-3-(+/-)-6, which are homologues of glutamic acid containing three additional carbon units. Moreover, because the potency of NMDA antagonists can be markedly increased by replacing the distal carboxylate with the bioisosteric phosphonate group, we also prepared the corresponding phosphonate derivatives (+/-)-7-(+/-)-10. All new compounds were submitted to binding assays with iGluRs, and derivatives (+/-)-3-(+/-)-6 were also tested in second messenger assays at representative mGluR subtypes. All the applied structural modifications were detrimental to the interaction with NMDA receptors. Conversely, structural variation of the nonselective mGluR ligand (+/-)-2 led to derivative (+/-)-5, which behaved as a selective group I metabotropic receptor antagonist. Notably, upon i.c.v. administration in DBA/2 mice, amino acid (+/-)-5 produced a significant protection against audiogenic seizures, whereas it was inactive after i.p. administration.
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ABSTRACT: A convenient synthesis of four new enantiomerically pure acidic amino acids is reported and their affinity at ionotropic glutamate receptors was determined. The new compounds are higher homologues of glutamic acid in which the molecular complexity has been increased by introducing an aromatic/heteroaromatic ring, that is a phenyl or a thiophene ring, that could give additional electronic interactions with the receptors. The results of the present investigation indicate that the insertion of an aromatic/heteroaromatic ring into the amino acid skeleton of glutamate higher homologues is well tolerated and this modification could be exploited to generate a new class of NMDA antagonists.Bioorganic & medicinal chemistry letters 03/2014; 24(8). DOI:10.1016/j.bmcl.2014.02.058 · 2.33 Impact Factor
ChemInform 03/2008; 39(10). DOI:10.1002/chin.200810204
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ABSTRACT: The kainate receptors are the least studied subfamily of ionotropic glutamate receptors. These receptors are thought to have a neuromodulatory role and have been associated with a variety of disorders in the central nervous system. This makes kainate receptors interesting potential drug targets. Today, structures of the ligand binding domain (LBD) of the kainate receptor GluK3 are only known in complex with the endogenous agonist glutamate, the natural product kainate, and two synthetic agonists. Herein we report structures of GluK3 LBD in complex with two 2,4-syn-functionalized (S)-glutamate analogues to investigate their structural potential as chemical scaffolds. Similar binding affinities at GluK3 were determined for the 2-(methylcarbamoyl)ethyl analogue (Ki=4.0 μM) and the 2-(methoxycarbonyl)ethyl analogue (Ki=1.7 μM), in agreement with the similar positioning of the compounds within the binding pocket. As the binding affinity is similar to that of glutamate, this type of Cγ substituent could be used as a scaffold for introduction of even larger substituents reaching into unexplored binding site regions to achieve subtype selectivity.ChemMedChem 10/2014; 9(10). DOI:10.1002/cmdc.201402204 · 3.05 Impact Factor