Medicinal Chemistry of Competitive Kainate Receptor Antagonists

Abstract

Kainic acid (KA) receptors belong to the group of ionotropic glutamate receptors and are expressed throughout in the central nervous system (CNS). The KA receptors have been shown to be involved in neurophysiological functions such as mossy fiber long-term potentiation (LTP) and synaptic plasticity and are thus potential therapeutic targets in CNS diseases such as schizophrenia, major depression, neuropathic pain and epilepsy. Extensive effort has been made to develop subtype-selective KA receptor antagonists in order to elucidate the physiological function of each of the five subunits known (GluK1-5). However, to date only selective antagonists for the GluK1 subunit have been discovered, which underlines the strong need for continued research in this area. The present review describes the structure-activity relationship and pharmacological profile for 10 chemically distinct classes of KA receptor antagonists comprising, in all, 45 compounds. To the medicinal chemist this information will serve as reference guidance as well as an inspiration for future effort in this field.Keywords: Glutamate receptors, kainic acid receptors, competitive antagonists, medicinal chemistry, structureactivity relationship studies T he common R-amino acid (S)-glutamate (Glu) functions as the major endogenous excitatory neurotransmitter in the central nervous system (CNS). Upon its release into the synaptic cleft, it activates the Glu receptors. These receptors have been divided into two major classes: the ligand-gated ion channels named the ionotropic receptors (iGluRs) and the slower acting G-protein coupled receptors named the metabotropic receptors (mGluRs). On the basis of ligand affinity studies, the class of iGluRs has been divided into three subgroups: the N-methyl-D-aspartate (NMDA), (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) and kainate (KA) receptors (1-3). With focus on the KA receptors, it is believed that this subgroup of receptors are potential therapeutic targets in diseases such as schizophrenia, major depression, pain, and epilepsy. In order to elucidate the role of the KA receptors, medicinal chemists have attempted to develop subtype-selective KA receptor ligands for the last two to three decades. Although extensive effort has been made, only a limited number of subtype-selective KA receptor ligands have been reported. For a comprehensive review on KA receptor agonists, see our recent review (4). The aim of this review is to provide the medicinal chemists (and others) who have an interest in the structure-activity relationship (SAR) of competitive KAR antagonists with an overview of the field. This information may aid the design of new subunit-selective KA receptor antagonists.

Binding site and interlobe interactions of the ionotropic glutamate receptor GluK3 ligand binding domain revealed by high resolution crystal structure in complex with (S)-glutamate

“…Within the kainate receptor subfamily numerous structures of the GluK1 LBD and several structures of the GluK2 LBD have been solved in complex with agonists: among others glutamate (Mayer, 2005), kainate (Plested et al, 2008), domoic acid (Hald et al, 2007), dysiherbaine (Frydenvang et al, 2009) and antagonists, such as ATPO (Hald et al, 2007) and compounds of UBP series (Alushin et al, 2010;Mayer et al, 2006). The structural information has provided key insights into biostructural mechanisms underlying receptor activation (Hald et al, 2007;Mayer, 2005) and continuously aids the design of new potential iGluR ligands (Larsen and Bunch, 2010;. Although there are no fully GluK3-selective ligands, many GluK1-selective compounds were shown to bind to GluK3 with a lower affinity, but not to GluK2 (Dargan et al, 2009;Jane et al, 2009).…”

Rapid Throughput Analysis Demonstrates that Chemicals with Distinct Seizurogenic Mechanisms Differentially Alter Ca2+ Dynamics in Networks Formed by Hippocampal Neurons in Culture

“…Although permeability to Ca 21 ions is usually small, it varies with subunit composition, and their slow activation and deactivation kinetics promote appreciable Ca 21 flux into postsynaptic neurons through NMDA receptor activation. The selective KAR agonist kainate is a naturally occurring excitatory amino acid commonly used in epilepsy research to induce seizures (Larsen and Bunch, 2011;Levesque and Avoli, 2013). After baseline recordings were completed, acute challenge of HN with a low concentration (0.1 mM) of kainate produced a rapid rise in baseline cytoplasmic Ca 21 (termed a Phase I response) whose magnitude was concentration dependent and did not return to the prechallenge baseline for the length (20 minutes) of the recording (Fig.…”

Synthesis and pharmacological characterization of the selective GluK1 radioligand (S)-2-amino-3-(6-[3H]-2,4-dioxo-3,4-dihydrothieno[3,2-d]pyrimidin-1(2H)-yl)propanoic acid ([3H]-NF608)

“…tert-Butyl (S)-(2-oxooxetan-3-yl)carbamate (2). To an icecooled solution of triphenylphosphine (95%, 7.3 g, 26.53 mmol) in anhydrous THF (50 mL), was added diethyl azidodicarboxylate (DEAD, 97%, 4.6 mL, 28.95 mmol).…”