Novel allosteric modulators of the M1 muscarinic acetylcholine receptor provide new insights into M1-dependent synaptic plasticity and receptor signaling

Abstract

Muscarinic acetylcholine receptors (mAChR) play important roles in regulating complex behaviors such as cognition, movement, and reward, making them ideally situated as potential drug targets for the treatment of several brain disorders. Recent advances in discovery of subtype selective allosteric modulators for mAChRs has provided an unprecedented opportunity for highly specific modulation of signaling of individual mAChR subtypes in the brain. Recently, allosteric modulators targeting the M1 mAChR have entered clinical development for Alzheimer’s disease and schizophrenia and have potential utility for other brain disorders. However, M1 mAChR allosteric modulators can display a diverse array of pharmacological properties and a more nuanced understanding of the mAChR is necessary to best translate preclinical findings into successful clinical treatments.