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

© 2018 American Chemical Society. The metabotropic glutamate 7 (mGlu 7 ) receptor belongs to the group III of mGlu receptors. Since the mGlu 7 receptor can control excitatory neurotransmission in the hippocampus and cortex, modulation of the receptor may have therapeutic benefit in several CNS diseases. However, mGlu 7 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 7 allosteric agonists. Hits originating from virtual screening were followed up with further analogue searching and screening, leading to a novel series of mGlu 7 allosteric agonists. Guided by docking into a structural model of the mGlu 7 receptor the initial hit 5 was successfully optimized to analogues with comparable potencies and more attractive drug-like attributes than AMN082.