A series of structurally novel heterotricyclic α‐amino‐3‐hydroxyl‐5‐methyl‐4‐isoxazole‐propionate receptor‐selective antagonists

Abstract

Background and purpose:A new class of heterotricyclic glutamate analogues recently was generated by incorporating structural elements of two excitotoxic marine compounds, kainic acid and neodysiherbaine A. Rather than acting as convulsants, several of these 'IKM' compounds markedly depressed CNS activity in mice. Here, we characterize the pharmacological profile of the series with a focus on the most potent of these molecules, IKM-159. Experimental approach: The pharmacological activity and specificity of IKM compounds were characterized using whole-cell patch clamp recording from neurons and heterologous receptor expression systems, in combination with radioligand binding techniques. Key results: The majority of the IKM compounds tested reduced excitatory synaptic transmission in neuronal cultures, and IKM-159 inhibited synaptic currents from CA1 pyramidal neurons in hippocampal slices. IKM-159 inhibited glutamate-evoked whole-cell currents from recombinant GluA2-and GluA4-containing a-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptors most potently, whereas kainate and NMDA receptor currents were not reduced by IKM-159. Antagonism of steady-state currents was agonist concentration dependent, suggesting that its mechanism of action was competitive, although it paradoxically did not displace [ Conclusions and implications:IKM-159 is an AMPA receptor-selective antagonist. IKM-159 and related nitrogen heterocycles represent structurally novel AMPA receptor antagonists with accessible synthetic pathways and potentially unique pharmacology, which could be of use in exploring the role of specific populations of receptors in neurophysiological and neuropathological processes.

Studies on an (S)-2-Amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic Acid (AMPA) Receptor Antagonist IKM-159: Asymmetric Synthesis, Neuroactivity, and Structural Characterization

“…9 This observation was consistent with its behavioral activity because other AMPA receptor antagonists, including the noncompetitive benzodiazepine GYKI52466 and its analogues 27 as well as the competitive quinoxaline ZK200775, 28 induce muscle relaxation and ataxia similar to IKM-159. To confirm that (2 R )-IKM-159 was the enantiomer responsible for AMPA receptor antagonism, we tested both (2 R ) and (2 S ) compounds in whole-cell patch clamp recordings of AMPA receptor excitatory postsynaptic currents (EPSCs) from cultured rat hippocampal neurons (Figure 4).…”

“…9 In order to clarify the mechanism of action and to gain insight into the molecular basis for the action of this chemically novel antagonist, we used X-ray crystallography to solve the structure of IKM-159 (from the racemic mixture) with the GluA2 LBD to 2.3 Å resolution (Table 1). Two dimers (A/C and B/D) were found in the asymmetric unit of the crystal, each dimer existing as a mixed dimer of one molecule containing (2 R )-IKM-159 in the binding site (molecules A and B) and the other molecule a sulfate or phosphate ion (modeled as sulfate; molecules C and D) (see Figure 5A).…”

“…9,13 However, previous biological studies were performed only on the racemates because no pathway was available for asymmetric synthesis. Here we report the first asymmetric synthesis and biological evaluation of both enantiomers of IKM-159.…”

Efficient synthesis of kainic acid analogues

“…[16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] In the planned derivatives, we always preserved the aminoacid moiety because the X-ray structural analyses of the iGluRs bilobular ligand-binding core in complex with agonists or antagonists evidenced the crucial role played by such a group. 31 In a recent paper, 32 it was described a series of derivatives generated by the incorporation of the structural elements of both kainic acid and neodysiherbaine A (neoDH), two naturally occurring pro-convulsant agents. Surprisingly, some of them, e.g.…”

“…32 On this ground, we designed the corresponding analogues of CIP-A and CIP-B in order to test their pharmacological profile and their selectivity versus AMPA receptor subtypes. The present paper deals with an improved synthesis of CIP-A and CIP-B and their transformation into CIOP-A and CIOP-B, the corresponding amido derivatives (Figure 2).…”