Discovery of a New Class of Ionotropic Glutamate Receptor Antagonists by the Rational Design of (2S,3R)-3-(3-Carboxyphenyl)-pyrrolidine-2-carboxylic Acid

Abstract

The kainic acid (KA) receptors belong to the class of glutamate (Glu) receptors in the brain and constitute a promising target for the treatment of neurological and/ or psychiatric diseases such as schizophrenia, major depression, and epilepsy. Five KA subtypes have been identified and named GluK1-5. In this article, we present the discovery of (2S,3R)-3-(3-carboxyphenyl)-pyrrolidine-2-carboxylic acid (1) based on a rational design process. Target compound 1 was synthesized by a stereoselective strategy in 10 steps from commercially available starting materials. Binding affinities of 1 at native ionotropic Glu receptors were determined to be in the micromolar range (AMPA, 51 μM; KA, 22 μM; NMDA 6 μM), with the highest affinity for cloned homomeric KA receptor subtypes GluK1,3 (3.0 and 8.1 μM, respectively). Functional characterization of 1 by two electrode voltage clamp (TEVC) electrophysiology at a nondesensitizing mutant of GluK1 showed full competitive antagonistic behavior with a K b of 11.4 μM.

Augmentation of Anticancer Drug Efficacy in Murine Hepatocellular Carcinoma Cells by a Peripherally Acting Competitive N-Methyl-d-aspartate (NMDA) Receptor Antagonist

“…25 Hereby, the 2,3- trans stereochemistry on the proline ring was set, and subsequent functional group transformations in accordance with earlier reported strategies ( 1d-f ; Scheme 2), ( 1g,h ; Scheme 3), ( 1i ;Scheme 4) and ( 1j ; Scheme 5), gave the free amino acids 1d-j ready for pharmacological evaluation. 23,24 …”

Structure–Activity Relationship Study of Ionotropic Glutamate Receptor Antagonist (2S,3R)-3-(3-Carboxyphenyl)pyrrolidine-2-carboxylic Acid

“…In terms of (a), the 2,4-cis position as well as the 4′-and 5′-positions appeared accessible based on synthetic methodology already described for this class of compounds. In terms of (b), the in silico predicted binding mode of antagonist 1 in the X-ray structure of GluA2-LBD with ATPO (PDB ID: 1N0T) ( Table 2) 30 suggests that a substituent in the 4′-position is directed into an area of the receptor presenting extensive hydrogen bonding capabilities, e.g., Ser673, Ser675, and Thr676 (GluA2 numbering with signal peptide), including harboring of a changing number of water molecules across the D1 and D2 domains. This area of the receptor is similar among the four GluA1−4 subunits but differs from and in between the five GluK1−5 subunits (Table 2).…”

“…For target compound 2a, the synthesis of suitably protected phenyl bromide 6a was synthesized starting from commercially available phenolic alcohol 12 (Scheme 2). 30 Reduction of the lactam functionality by borane gave pyrrolidinone 8a in low-to-acceptable yield (32−46%), with the byproduct being reductive opening of the isopropylidene group (determined by LC-MS). At this stage, a shortcut was attempted: full deprotection of pyrrolidinone 8a in p-TsOH/MeOH at room temperature (rt) gave the expected phenolic diol 13 in high yield (Scheme 3 Scheme 2.…”

Blood–Brain Barrier Permeability and Brain Uptake Mechanism of Kainic Acid and Dihydrokainic Acid

“…Both molecules have been used as research tools in various in vivo CNS disease models in rodents, such as; epilepsy, Huntington's, Parkinson's and Alzheimer's diseases [1][2][3][4][5], as well as being templates in the design of novel ligands affecting the glutamatergic system [6,7]. The glutamatergic neurotransmitter system is involved in many important neurophysiological processes and thus constitutes a promising target for the treatment of neurological diseases such, as Parkinson's disease and epilepsy [8,9].…”