Molecular mechanism of positive allosteric modulation of the metabotropic glutamate receptor 2 by JNJ-46281222.

ABSTRACT:

Background and purpose

Allosteric modulation of the mGlu2 receptor is a potential strategy for treatment of various neurological and psychiatric disorders. Here, we describe the in vitro characterization of the mGlu2 positive allosteric modulator (PAM) JNJ-46281222 and its radiolabelled counterpart [(3) H]-JNJ-46281222. Using this novel tool, we also describe the allosteric effect of orthosteric glutamate binding and the presence of a bound G protein on PAM binding and use computational approaches to further investigate the binding mode.

Experimental approach

We have used radioligand binding studies, functional assays, site-directed mutagenesis, homology modelling and molecular dynamics to study the binding of JNJ-46281222.

Key results

JNJ-46281222 is an mGlu2 -select

SUBMITTER: Doornbos ML 

PROVIDER: S-EPMC4728424 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature