Kainic Acid-Based Agonists of Glutamate Receptors: SAR Analysis and Guidelines for Analog Design

Abstract

A comprehensive survey of kainic acid analogs that have been tested for their biological activity is presented. Specifically, this review (1) gathers and compares over 100 kainoids according to a relative activity scale, (2) exposes structural features required to optimize affinity for kainate receptors, and (3) suggests design rules to create next-generation KA analogs. Literature SAR data are analyzed systematically and combined with the most recent crystallographic studies. In view of the renewed interest in neuroactive molecules, this review aims to help guide the efforts of organic synthesis laboratories, as well as to inform newcomers to KA/GluK research.

Current Trends and New Challenges in Marine Phycotoxins

“…Each subunit has three transmembrane regions (M1, M3, and M4) with a partial re-entering loop from the cytoplasm to the membrane. Two large extracellular domains are also defined, i.e., the N-terminal domain and ligand-binding domain (LBD) [ 149 , 150 ]. The structure of DA binding to rat kainate receptors GluK1 (former GluR5) LBD and GluK2 (former GluR6) LBD has been determined at a high resolution [ 148 , 151 , 152 ].…”

“…LBD has a clamshell form to which DA binds between the two “shells” (lobes). Afterwards, it partially closes, leading to channel opening and calcium entrance [ 149 , 150 ]. However, these structures are based on LBD soluble form; thus, these conformation modifications are to be confirmed by elucidating DA structure bound to full length receptors.…”

Aminooxadiazolyl kainic acid reveals that kainic acid receptors contribute to astrocytoma glutamate signaling

“…17 The parent natural product, kainic acid, has been widely used as a chemical tool in neurobiology. 17,[20][21][22] Below is described the synthesis of AODKA as lead compound for a novel class of heteroaromatic KA analogs (Scheme 1).…”

“…Based on our practical synthesis of kainoid analogs, we designed a C4-heteroaryl kainoid that was expected to be more potent than its parent natural product kainic acid. 17,19,20 Our previous SAR analysis 12 suggested that C4-aryl kainoids are highly potent KAR agonists, mostly due to the C4 substituent participating in π-π stacking with a key phenol side chain within the binding pocket (Tyr448, Figure 3). Aminooxazolyl kainoid 1 was selected for two main reasons: (1) its electron-deficient quadrupole would complement and enhance π-π stacking interactions with Tyr488, and (2) the 2amino substituent would allow easy attachment of different molecular cargo to create new chemical biology tools (e.g., fluorescent tags, biotin, photoswitch, etc.…”

Optical Control of Ca2+-Mediated Morphological Response in Glial Cells with Visible Light Using a Photocaged Kainoid

“…This secondary amine is essential to the binding of kainic acid analogs to the KAR protein, thus, protecting it makes 1 biologically inactive. 26 As cage moiety, we selected a 7-N,N-diethylaminocoumarin (DECM) carbamate because it can be cleaved by blue light sources equipped on most modern microscopes to release phenylkainic acid (PhKA, 2) as active KAR agonist. Consequently, DECM-PhKA should act as a "turn-on" probe to study KAR activity in living cells.…”