Beschreibung:
<jats:p>Non‐selective antagonists of muscarinic acetylcholine receptors (mAChRs) that broadly inhibit all five mAChR subtypes provide an efficacious treatment for some movement disorders, including Parkinson’s disease and dystonia. Despite their efficacy in these and other central nervous system disorders, anti‐muscarinic therapy has limited utility due to severe adverse effects that often limit their tolerability by patients. Recent advances in understanding the roles that each mAChR subtype plays in disease pathology suggest that highly selective ligands for individual subtypes may underlie the anti‐parkinsonian and anti‐dystonic efficacy observed with the use of non‐selective anti‐muscarinic therapeutics. Our recent work has indicated that the M4 muscarinic acetylcholine receptor has several important roles in opposing aberrant neurotransmitter release, intracellular signaling pathways, and brain circuits associated with movement disorders. This raises the possibility that selective antagonists of M4 may recapitulate the efficacy of non‐selective anti‐muscarinic therapeutics and may decrease or eliminate the adverse effects associated with these non‐selective drugs. However, this hypothesis has not been directly tested due to lack of selective antagonists of M4. Here we utilize genetic mAChR knockout animals in combination with non‐selective mAChR antagonists to confirm that the M4 receptor underlies the locomotor‐stimulating and anti‐parkinsonian efficacy in rodent models. We also report the synthesis, discovery, and characterization of a series of first‐in‐class selective M4 antagonists. These novel compounds have ideal pharmacokinetic properties for in vivo evaluations, and we have confirmed that these optimized compounds have anti‐parkinsonian and anti‐dystonic efficacy in pharmacological and genetic models of movement disorders. These data provide critical pre‐clinical rationale for the development of M<jats:sub>4</jats:sub> antagonists and represent a potential novel treatment mechanism to meet the unmet clinical need across several movement disorders.</jats:p>