Mechanisms of Allosteric Modulation at the Muscarinic Acetylcholine Receptors

The muscarinic acetylcholine receptors (mAChRs) are potential drug targets for many disorders including Alzheimer’s disease and schizophrenia. Unfortunately, it is difficult to develop therapeutics that selectively target one mAChR subtype at the neurotransmitter binding site as the five subtypes are highly similar. Promisingly, allosteric modulators that bind to a spatially distinct allosteric binding site can display subtype selectivity. To further advance allosteric modulators as viable therapeutics, this thesis determines mechanisms of allostery through pharmacology and structural biology techniques. A better molecular understanding of the mechanisms that underpin allosteric modulator activity will facilitate the development of novel mAChR therapeutics.