4MF3

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

Summary for 4MF3

• Entry DOI: 10.2210/pdb4mf3/pdb
• Descriptor: Glutamate receptor ionotropic, kainate 1, (3S,4aS,6S,8aR)-6-[3-chloro-2-(1H-tetrazol-5-yl)phenoxy]decahydroisoquinoline-3-carboxylic acid (3 entities in total)
• Functional Keywords: protein-ligand complex, ligand gated ion channel, glutamate receptor, glutamate binding, none, membrane, signaling protein
• Biological source: Homo sapiens (human); More
• Cellular location: Cell membrane; Multi-pass membrane protein: P39086
• Total number of polymer chains: 2
• Total formula weight: 59973.57

Authors

Martinez-Perez, J.A.,Iyengar, S.,Shannon, H.E.,Bleakman, D.,Alt, A.,Clawson, D.K.,Arnold, B.M.,Bell, M.G.,Bleisch, T.J.,Castano, A.M.,Del Prado, M.,Dominguez, E.,Escribano, A.M.,Filla, S.A.,Ho, K.H.,Hudziak, K.J.,Jones, C.K.,Katofiasc, M.A.,Mateo, A.,Mathes, B.M.,Mattiuz, E.L.,Ogden, A.M.L.,Phebus, L.A.,Simmons, R.M.A.,Stack, D.R.,Stratford, R.E.,Winter, M.A.,Wu, Z.,Ornstein, P.L. (deposition date: 2013-08-27, release date: 2014-05-07, Last modification date: 2024-11-06)

Primary citation

Martinez-Perez, J.A.,Iyengar, S.,Shannon, H.E.,Bleakman, D.,Alt, A.,Clawson, D.K.,Arnold, B.M.,Bell, M.G.,Bleisch, T.J.,Castano, A.M.,Del Prado, M.,Dominguez, E.,Escribano, A.M.,Filla, S.A.,Ho, K.H.,Hudziak, K.J.,Jones, C.K.,Mateo, A.,Mathes, B.M.,Mattiuz, E.L.,Ogden, A.M.,Simmons, R.M.,Stack, D.R.,Stratford, R.E.,Winter, M.A.,Wu, Z.,Ornstein, P.L.
GluK1 antagonists from 6-(tetrazolyl)phenyl decahydroisoquinoline derivatives: in vitro profile and in vivo analgesic efficacy.
Bioorg.Med.Chem.Lett., 23:6463-6466, 2013

PubMed Abstract: 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.

PubMed: 24140446
DOI: 10.1016/j.bmcl.2013.09.045

Experimental method

X-RAY DIFFRACTION (3 Å)