The muscarinic acetylcholine receptors (mAChR) regulate many vital functions of the central and peripheral nervous systems1. As such, they are important drug targets for various CNS disorders like Alzheimer’s disease, schizophrenia, and drug addiction 2-3.
Due to high sequence identity and structural homology among the five mAChRs it has been difficult to design selective drugs targeting an individual subtype. Although there are a few reports of subtype selective drugs, such as PCS10555, the structural basis of selective drug action at the mAChRs remains unknown.
Therefore, the aim of this study was to try and determine a structure of either the M4 receptor bound to the selective antagonist PCS1055, or the M5 receptor with the selective negative allosteric modulator (NAM) ML375. We also report our recent progress towards determining if PEG400 is an allosteric modulator of the M5 receptor.
PCS1055 is a recently described M4 selective antagonist (PCS1055) that inhibits radioligand [3H]-NMS binding to the M4 receptor with a Ki of 6.5 nM. And ML3756 is a M5 selective NAM that has an IC50 of 1.2 uM in calcium mobilisation assay.