Subtype selective kainic acid receptor agonists: Discovery and approaches to rational design

  title={Subtype selective kainic acid receptor agonists: Discovery and approaches to rational design},
  author={Lennart Bunch and Povl Krogsgaard‐Larsen},
  journal={Medicinal Research Reviews},
(S)‐Glutamic acid (Glu) is the major excitatory neurotransmitter in the mammalian central nervous system, activating the plethora of glutamate receptors (GluRs). In broad lines, the GluRs are divided into two major classes: the ionotropic Glu receptors (iGluRs) and the metabotropic Glu receptors (mGluRs). Within the iGluRs, five subtypes (KA1, KA2, iGluR5‐7) show high affinity and express full agonist activity upon binding of the naturally occurring amino acid kainic acid (KA). Thus these… 
Medicinal chemistry of competitive kainate receptor antagonists.
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 and will serve as reference guidance as an inspiration for future effort in this field.
Kainic acid-based agonists of glutamate receptors - SAR analysis and guidelines for analogs design.
This review gathers and compares over one hundred kainoids according to a relative potency scale, exposes the structural features required to optimize affinity for kainate receptors, and suggests design rules to create next-generation KA analogs.
Discovery of a new class of ionotropic glutamate receptor antagonists by the rational design of (2S,3R)-3-(3-carboxyphenyl)-pyrrolidine-2-carboxylic acid.
The discovery of (2S,3R)-3-(3- carboxyphenyl)-pyrrolidine-2-carboxylic acid (1) is presented based on a rational design process and Binding affinities of 1 at native ionotropic Glu receptors were determined to be in the micromolar range.
Excitatory amino acid transporters as potential drug targets
Not until subtype-selective enhancers, inhibitors and substrates for all five EAAT subtypes have been discovered can a full and detailed understanding of EAATs be obtained, so collaboration between organic chemists and molecular pharmacologists, together, may pave the way for new EAAT ligands of importance.
Design and Synthesis of 2,3- trans-Proline Analogues as Ligands for Ionotropic Glutamate Receptors and Excitatory Amino Acid Transporters.
The synthesis of 18 analogues of (2 S,3 R)-2-carboxy-3-pyrrolidine acetic acid (3a) is reported, which explores the effect of introducing a substituent on the ε-carbon (3c-q) in order to study the role and function of these receptors in the central nervous system.
Chemoenzymatic synthesis of new 2,4-syn-functionalized (S)-glutamate analogues and structure-activity relationship studies at ionotropic glutamate receptors and excitatory amino acid transporters.
Two X-ray crystal structures of the key analogue 2i in the ligand-binding domain (LBD) of GluA2 and GluK3 were determined and partial domain closure was seen in the GLUA2-LBD complex with 2i comparable to that induced by kainate.
Excitatory Amino Acids and Their Antagonists
EAAs are usually grouped to distinguish them from AAs like GABA, Glycine, or Taurine exerting inhibitory effects on neuronal cells, and in the periphery EAAs contribute to the regulation of gastrointestinal motility, pain sensation, and respiratory and cardiovascular functions.
Synthesis and pharmacological characterization of the selective GluK1 radioligand (S)-2-amino-3-(6- [H]-2,4-dioxo-3,4-dihydrothienoij3,2-d]pyrimidin- 1IJ2H)-yl)propanoic acid ([H]-NF608)†‡
Binding affinities of a series of standard GluK1 ligands were shown to be in line with previously reported affinITIES obtained by use of already reported radioligands.
Blood–Brain Barrier Permeability and Brain Uptake Mechanism of Kainic Acid and Dihydrokainic Acid
The non-specific plasma and brain protein binding of KA and DHK was determined to be low, which means that the unbound drug volume of distribution in brain is also low, and even though the total KAand DHK concentrations in the brain are low after systemic dosing, the concentration in the vicinity of the glutamate receptors are sufficient for their activation and thus the observed efficacy.