We are developing emraclidine for the treatment of both schizophrenia and Alzheimer’s disease psychosis. Emraclidine was rationally designed as a positive allosteric modulator (PAM) that selectively targets the muscarinic acetylcholine 4 receptor subtype (M4) to harness the potential anti-psychotic benefit believed to be associated with M4 while minimizing the side effects typically associated with pan-muscarinic agonists.
About the Mechanism of Emraclidine
Schizophrenia is a serious, complex and debilitating mental health disorder characterized by a constellation of symptoms, including delusions, hallucinations, disorganized speech or behavior, slowed speech and blunted affect.
One of the leading theories on the etiology of schizophrenia is that an overactivity of dopamine in certain brain regions is closely associated with the prevailing psychotic symptoms. Current antipsychotics target a direct blockade of dopamine receptors. While this approach is effective at reducing symptoms, it also leads to significant side effects.
Presynaptic expression of the M4 receptor subtypes balances acetylcholine and dopamine in the striatum, which is the region of the brain primarily responsible for psychotic symptoms. The imbalance of acetylcholine and dopamine is hypothesized to contribute to psychosis in schizophrenia. Unlike other muscarinic receptors, M4 receptor subtypes are differentially expressed in the striatum. Activation of muscarinic receptors prevents acetylcholine release, which has been shown to indirectly modulate levels of dopamine without the direct D2/D3 receptor blockade that has been theorized to cause some of the unwanted motor symptoms of current antipsychotics.
Thus, selective activation of M4 has the potential to be effective in the treatment of the neurobehavioral components such as psychosis, agitation and cognitive deficits that are associated with schizophrenia and other neurodegenerative diseases like Alzheimer’s disease psychosis, while potentially mitigating some of the side effects of current antipsychotics.
Emraclidine is a selective M4 receptor PAM, meaning it selectively targets the M4 receptor to harness the anti-psychotic effect believed to be associated with this receptor while minimizing the side effects associated with other pan-muscarinic agonists. We believe emraclidine has the potential to provide a significant medical advancement as the muscarinic acetylcholine pathway has long been associated with mediation of neurotransmitter imbalance and psychosis. To our knowledge, emraclidine is the only selective M4 receptor PAM currently in clinical development.
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