Modulation of the M4 muscarinic receptor for the treatment of schizophrenia

Schizophrenia is a debilitating psychiatric disorder that affects ~1% of the world’s population. All current antipsychotic drugs act as D2 receptor antagonists. Unfortunately, these provide only partial symptom relief and often trigger prominent side effects. Additionally, almost 30% of schizophrenic patients are un-responsive to current antipsychotic medications. Sadly, these limitations contribute to the current reality that >70% of patients discontinue their antipsychotic treatment within the first 18 months. The M4 muscarinic acetylcholine receptor (mAChR) has recently emerged as a promising target for the treatment of schizophrenia. A recent clinical trial using Xanomeline, a selective M1/M4 orthosteric agonist, showed reduced psychotic symptoms in schizophrenic patients, successfully progressing through to Phase 3 clinical trial. Additionally, Emraclidine, a selective M4 allosteric modulator, able to target the M4 mAChR through an alternative binding site, has also showed significant positive outcomes in a Phase 1b clinical trial.
Here, we propose to build a comprehensive study on the molecular, cellular and physiological outcomes of Xanomeline and Emraclidine at the M4 mAChR for the treatment of schizophrenia. We will 1) solve multiple M4 mAChR structures bound to Emraclidine and either ACh or Xanomeline, 2) explore the modulatory effect of Emraclidine on Xanomeline and ACh in multiple G protein dependent and independent pathways, 3) validate the modulatory effect of Emraclidine with ACh and xanomeline in native systems and multiple pre-clinical models of schizophrenia, and 4) design and synthesise the next generation of selective M4 mAChR ligands by developing compounds that simultaneously explore the orthosteric and allosteric chemical spaces.