Cognitive effects of muscarinic M1 functional agonists in non-human primates and clinical trials

The limited effect of AChE inhibitors and NMDA receptor antagonists for the treatment of the cognitive symptoms of Alzheimer's disease has prompted the search for new drugs that are capable not only of treating behavioral symptoms, but also of modifying the disease process. Considerable research efforts have been focused on orthosteric muscarinic M1 functional agonists during the past decade to address both these strategies. Part of this research has included the use of non-human primates as models of cognitive impairment to demonstrate preclinical efficacy. No M1 functional agonist has been successfully registered for the treatment of Alzheimer's disease, mostly because of mechanism-related adverse side effects and marginal cognitive effects. However, the M1 agonist xanomeline exhibited preclinical and clinical efficacy for the treatment of the negative and cognitive symptoms of schizophrenia. These results prompted renewed interest in repositioning compounds such as sabcomeline (Proximagen Group plc) for this indication, as well as developing allosteric muscarinic M1 ligands to improve efficacy while reducing side-effect-related attrition. This review discusses preclinical and clinical data from orthosteric M1 functional agonists, focusing on target validation in primate cognition studies, and provides recommendations for testing a new generation of M1 ligands and compounds with novel mechanisms of action.