Structural determinants of allosteric antagonism at metabotropic glutamate receptor 2: mechanistic studies with new potent negative allosteric modulators.

ABSTRACT:

Background and purpose

Altered glutamatergic neurotransmission is linked to several neurological and psychiatric disorders. Metabotropic glutamate receptor 2 (mGlu₂) plays an important role on the presynaptic control of glutamate release and negative allosteric modulators (NAMs) acting on mGlu₂/₃ receptors are under assessment for their potential as antidepressants, neurogenics and cognitive enhancers. Two new potent mGlu₂/₃ NAMs, RO4988546 and RO5488608, are described in this study and the allosteric binding site in the transmembrane (TM) domain of mGlu₂ is characterized.

Experimental approach

Site directed mutagenesis, functional measurements and β₂-adrenoceptor-based modelling of mGlu₂ were employed to identify important molecular determinants of two new potent mGlu₂/₃ NA

SUBMITTER: Lundstrom L 

PROVIDER: S-EPMC3188907 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature