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Selective Negative Allosteric Modulation Of Metabotropic Glutamate Receptors - A Structural Perspective of Ligands and Mutants

Publication: Research - peer-reviewJournal article

Kasper Harpsøe, Vignir Isberg, Benjamin G Tehan, Dahlia Weiss, Angela Arsova, Fiona H Marshall, Hans Bräuner-Osborne, David E Gloriam

The metabotropic glutamate receptors have a wide range of modulatory functions in the central nervous system. They are among the most highly pursued drug targets, with relevance for several neurological diseases, and a number of allosteric modulators have entered clinical trials. However, so far this has not led to a marketed drug, largely because of the difficulties in achieving subtype-selective compounds with desired properties. Very recently the first crystal structures were published for the transmembrane domain of two metabotropic glutamate receptors in complex with negative allosteric modulators. In this analysis, we make the first comprehensive structural comparison of all metabotropic glutamate receptors, placing selective negative allosteric modulators and critical mutants into the detailed context of the receptor binding sites. A better understanding of how the different mGlu allosteric modulator binding modes relates to selective pharmacological actions will be very valuable for rational design of safer drugs.

Original languageEnglish
Article number13869
JournalScientific Reports
Volume5
Pages (from-to)1-11
Number of pages11
ISSN2045-2322
DOIs
StatePublished - 11 Sep 2015

ID: 144697865