Selective Positive Allosteric Modulation for the M1 Muscarinic Receptor: discovery and development of compound VU0486846 and its importance for the development of treatments for Alzheimer's and Schizophrenia

Objective: Conduct a systematic review of therapeutic development strategies for Alzheimer's disease and schizophrenia based on positive allosteric modulation of the M-1 receptor. Method: A systematic review of articles on Pubmed, Ebsco and Science Direct was carried out, from 2015, following established guidelines for selecting keywords, inclusion and exclusion criteria Results: A total of 44 articles met the established criteria, 20 of them are reviews and 11 are publications where one or more compounds are synthesized and pharmacologically evaluated. Half of the publications that conduct an in vivo evaluation are in publications of the Center for the Discovery of Drugs in Neurosciences of Vanderbilt University. Its main discovery, the compound VU0486846, is the newest and most important derivative result of a line of therapeutic advances based on the allosteric activation of the M-1 receptor, which has no direct agonist activity on muscarinic receptors but if can positively modulate the activity of acetylcholine on the M-1 receptor, demonstrating absence of severe cholinergic adverse effects in animal models. Searching for molecule derivatives with higher property balance does not provide a better candidate. Conclusions: The development of compound VU0486846 corresponds to an important milestone in the search for treatments for Alzheimer's disease and schizophrenia. The success of this molecule and its research route is a validation of the pharmacological importance of allosteric modulation in the search for new pharmacological targets.