molecules of the month

Emraclidine (CVL-231) is a selective positive allosteric modulator (PAM) of the cholinergic M4 muscarinic receptor and is the only selective M4 PAM in clinical development. The molecule has shown promising early results in schizophrenia with several Ph. II trials enrolling and is intended to be developed for Alzheimer’s Disease psychosis as well. The molecule is highly brain penetrant and has shown clear target engagement based on PET studies in non-human primates. The role of M4 in treating psychosis has validation from clinical studies from the ‘90s with M1/M4 agonist xanomeline, which was not further developed due to side effects. With its >390x selectivity for M4 over other muscarinic receptors and more moderate positive allosteric modulator mechanism vs. full agonism, emraclidine…