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; competitive antagonists; kainic acid receptors; medicinal chemistry; structure−activity relationship studies.

Figure 1

(A) Cartoon illustration of an iGluR showing the four regions: the carboxylate terminal domain (CTD), the transmembrane domain (TMD), the ligand binding domain (LBD), and the amino terminal domain (ATD). (B) Cartoon illustration of uniform assembly (hetero tetramer A) or opposite assembly (hetero tetramer B) of two heterodimers of GluK1 and GluK5. Black triangle illustrates the LBD.

Figure 2

Schematic representation of the ligand-binding domain (LBD) of GluK1 as a clam shell: In its open free form (apo state), an agonist may bind, which facilitates closure of the shell and opening of the ion channel (agonist state). Depending on the nature of the agonist, the receptor may enter a desensitized closed state in which the ion channel is blocked. Subsequent release of the agonist renders the receptor available in the free apo state via an intermediate desensitized open state. An antagonist captures and stabilizes the apo state of the receptor (antagonist state), thus keeping the ion channel closed.

Figure 3

Chemical structures of compounds 10.1−10.4.