4mf3

Crystal Structure of Human GRIK1 complexed with a 6-(tetrazolyl)aryl decahydroisoquinoline antagonist

spinqualitylabelsall models 4mf3, resolution 3.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4mf3 is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: SXI Gene: GRIK1, GLUR5 (HUMAN) Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [GRIK1_HUMAN] 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. Publication Abstract from PubMed We have explored the decahydroisoquinoline scaffold, bearing a phenyl tetrazole, as GluK1 antagonists with potential as oral analgesics. We have established the optimal linker atom between decahydroisoquinoline and phenyl rings and demonstrated an improvement of both the affinity for the GluK1 receptor and the selectivity against the related GluA2 receptor with proper phenyl substitution. In this Letter, we also disclose in vivo data that led to the discovery of LY545694.HCl, a compound with oral efficacy in two persistent pain models. GluK1 antagonists from 6-(tetrazolyl)phenyl decahydroisoquinoline derivatives: in vitro profile and in vivo analgesic efficacy.,Martinez-Perez JA, Iyengar S, Shannon HE, Bleakman D, Alt A, Clawson DK, Arnold BM, Bell MG, Bleisch TJ, Castano AM, Del Prado M, Dominguez E, Escribano AM, Filla SA, Ho KH, Hudziak KJ, Jones CK, Mateo A, Mathes BM, Mattiuz EL, Ogden AM, Simmons RM, Stack DR, Stratford RE, Winter MA, Wu Z, Ornstein PL Bioorg Med Chem Lett. 2013 Dec 1;23(23):6463-6. doi: 10.1016/j.bmcl.2013.09.045. , Epub 2013 Sep 24. PMID:24140446 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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