| Structural highlights
Function
[GRIK1_RAT] Ionotropic glutamate receptor. L-glutamate acts as an excitatory neurotransmitter at many synapses in the central nervous system. Binding of the excitatory neurotransmitter L-glutamate induces a conformation change, leading to the opening of the cation channel, and thereby converts the chemical signal to an electrical impulse. The receptor then desensitizes rapidly and enters a transient inactive state, characterized by the presence of bound agonist. May be involved in the transmission of light information from the retina to the hypothalamus.[1]
Publication Abstract from PubMed
Ionotropic glutamate receptor antagonists are valuable tool compounds for studies of neurological pathways in the central nervous system. On the basis of rational ligand design, a new class of selective antagonists, represented by (2S,4R)-4-(2-carboxyphenoxy)pyrrolidine-2-carboxylic acid (1b), for cloned homomeric kainic acid receptors subtype 1 (GluK1) was attained (Ki = 4 muM). In a functional assay, 1b displayed full antagonist activity with IC50 = 6 +/- 2 muM. A crystal structure was obtained of 1b when bound in the ligand binding domain of GluK1. A domain opening of 13-14 degrees was seen compared to the structure with glutamate, consistent with 1b being an antagonist. A structure-activity relationship study showed that the chemical nature of the tethering atom (C, O, or S) linking the pyrrolidine ring and the phenyl ring plays a key role in the receptor selectivity profile and that substituents on the phenyl ring are well accommodated by the GluK1 receptor.
Design and Synthesis of a Series of l-trans-4-Substituted Prolines as Selective Antagonists for the Ionotropic Glutamate Receptors Including Functional and X-ray Crystallographic Studies of New Subtype Selective Kainic Acid Receptor Subtype 1 (GluK1) Antagonist (2S,4R)-4-(2-Carboxyphenoxy)pyrrolidine-2-carboxylic Acid.,Krogsgaard-Larsen N, Delgar CG, Koch K, Brown PM, Moller C, Han L, Huynh TH, Hansen SW, Nielsen B, Bowie D, Pickering DS, Kastrup JS, Frydenvang K, Bunch L J Med Chem. 2017 Jan 12;60(1):441-457. doi: 10.1021/acs.jmedchem.6b01516. Epub, 2016 Dec 22. PMID:28005385[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Mayer ML, Ghosal A, Dolman NP, Jane DE. Crystal structures of the kainate receptor GluR5 ligand binding core dimer with novel GluR5-selective antagonists. J Neurosci. 2006 Mar 15;26(11):2852-61. PMID:16540562 doi:26/11/2852
- ↑ Krogsgaard-Larsen N, Delgar CG, Koch K, Brown PM, Moller C, Han L, Huynh TH, Hansen SW, Nielsen B, Bowie D, Pickering DS, Kastrup JS, Frydenvang K, Bunch L. Design and Synthesis of a Series of l-trans-4-Substituted Prolines as Selective Antagonists for the Ionotropic Glutamate Receptors Including Functional and X-ray Crystallographic Studies of New Subtype Selective Kainic Acid Receptor Subtype 1 (GluK1) Antagonist (2S,4R)-4-(2-Carboxyphenoxy)pyrrolidine-2-carboxylic Acid. J Med Chem. 2017 Jan 12;60(1):441-457. doi: 10.1021/acs.jmedchem.6b01516. Epub, 2016 Dec 22. PMID:28005385 doi:http://dx.doi.org/10.1021/acs.jmedchem.6b01516
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