Discovery of oxazolidinone-based heterocycles as subtype selective sigma-2 ligands

The sigma-2 (σ2) receptor, also known as the Transmembrane Protein 97 (TMEM97, and MAC30 (Meningioma-associated protein), has been linked to a number of conditions are disease states such schizophrenia, cancer, Alzheimer’s disease, traumatic brain injury, neuropathic pain. As part or our on-going effort identify novel σ2 ligands, we have identified series novel, functionalized oxazolidin-2-one ligands (4). Our lead compound (4h) demonstrated high affinity (Ki = 36 nM) excellent σ1/σ2 selectivity (79-fold). Evaluation its at key CNS targets via Psychoactive Drug Screening Program (PDSP) indicated degree for over other receptors.