Exploration of structure-based drug design opportunities for mGluRs.

The metabotropic glutamate receptors (mGluRs) are a subset of the Class C G-Protein Coupled Receptors (GPCRs). Recently, an emerging strategy for drug-discovery efforts targeting mGluRs has been to develop compounds acting at the so-called allosteric site in the 7-transmembrane (7TM) domain, common to all GPCRs, rather than the extracellular (EC) domain containing the orthosteric glutamate-binding site. We examine herein some of the intrinsic relative merits of targeting these two domains. Comparisons are made among amino-acid sequences in the two domains and among X-ray structures and homology models of the EC domain. We show that there is greater sequence diversity in the EC domains than in the transmembrane (TM) domains. Thus, contrary to generally accepted descriptions of there being greater evolutionary pressure to preserve the EC domain, it is the 7TM domain that is more highly conserved. Within the EC domain, the glutamate-binding site of the Venus flytrap region has hitherto received the most attention as a target site. Analysis of examples of the three-dimensional structures of the EC domains at the glutamate-binding site reveals differences as well, thereby supporting the viability of targeting the EC domain, even at the glutamate-binding site, for drug discovery. To exemplify this strategy, we present examples of active compounds identified via high-throughput docking in the EC region.