Ehud Isacoff

FRET Screen for Glutamate Receptor Modulators for Treatment of Depression

Major depressive disorder is a debilitating and illness for which ~9 million Americans receive treatment yearly, approximately one third suffering from treatment-resistant depression. Established antidepressants require weeks to act. In contrast, ketamine, a blocker of NMDA receptors (NMDARs), acts quickly with high efficacy and has become a billion-dollar drug. However, ketamine suffers from severe side effects (hallucinations, cognitive impairment) due to poor selectivity between heteromeric NMDAR subtypes. Metabotropic glutamate receptors (mGluRs) are also promising targets, but drugs that target mGluR homodimers have failed trial, likely because they are not aimed at the heterodimeric receptors that operate at synapses. The team’s goal is to discover negative and positive allosteric modulators that selectively target heteromeric NMDARs and mGluRs that are implicated in depression. They have developed a unique HTS screening platform that uses fluorescence resonance energy transfer (FRET) todetect structural rearrangements that transition receptors from low to high signaling states, providing a robust screen for allosteric modulators (patent pending). Preliminary multiwell-plate assays in the Berkeley Drug Discovery Center (DCC), supported by an MTI Innovator award, provide high-SNR endpoint dose-response curves and strong signatures of known positive and negative allosteric modulators in both cell-based and protein-based formats on a standard plate reader. Bakar support will enable pilot and large-scale screens (1,200 FDA-approved and other 100,000+ compound libraries available through the DDC), and subsequent specificity and validation studies, on three depression-implicated targets. During Bakar support, they will initiate lead optimization studies and seek funding to launch a company.