Computationally Guided Identification of Allosteric Agonists of the Metabotropic Glutamate 7 Receptor.

The metabotropic glutamate 7 (mGlu) receptor belongs to the group III of mGlu receptors. Since the mGlu receptor can control excitatory neurotransmission in the hippocampus and cortex, modulation of the receptor may have therapeutic benefit in several CNS diseases. However, mGlu remains relatively unexplored among the eight known mGlu receptors partly because of the limited availability of tool compounds to interrogate its potential therapeutic utility. Here we report the discovery of a new class of mGlu allosteric agonists. Hits originating from virtual screening were followed up with further analogue searching and screening, leading to a novel series of mGlu allosteric agonists. Guided by docking into a structural model of the mGlu receptor the initial hit 5 was successfully optimized to analogues with comparable potencies and more attractive drug-like attributes than AMN082.