Orthosteric versus allosteric GPCR activation: the great challenge of group-III mGluRs

Biochemical Pharmacology
Peter J Flor, Francine Acher

Abstract

Group-III metabotropic glutamate receptors (mGluRs) comprise four structurally related brain and retinal G protein-coupled receptors (GPCRs), mGluR4, mGluR6, mGluR7 and mGluR8, which receive much attention as promising targets for nervous system drugs. In particular, activation of mGluR4 is a major focus for the development of new therapeutics in Parkinson's disease, while mGluR7 activation is considered a potential approach for future treatments of specific psychiatric conditions. The first generation group-III mGluR agonists, e.g.l-AP4 and l-SOP, are characterized by an essential phosphonate functional group, which became a major limitation for the development of systemically active, potent and receptor subtype-selective drugs. Recently however, two approaches emerged in parallel providing resolution to this constraint: in silico high-throughput screening of chemical libraries against a 3D-model of the mGluR4 extracellular domain identified a hit that was optimized into a series of potent and subtype-selective orthosteric agonists with drug-like properties and novel chemotype structures; secondly, high-throughput random screening of chemical libraries against recombinantly expressed group-III receptors identified diverse chem...Continue Reading

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