posted on 2021-08-02, 15:37authored byMark S. Moehle, Aaron M. Bender, Jonathan W. Dickerson, Daniel J. Foster, Aidong Qi, Hyekyung P. Cho, Yuping Donsante, Weimin Peng, Zoey Bryant, Kaylee J. Stillwell, Thomas M. Bridges, Sichen Chang, Katherine J. Watson, Jordan C. O’Neill, Julie L. Engers, Li Peng, Alice L. Rodriguez, Colleen M. Niswender, Craig W. Lindsley, Ellen J. Hess, P. Jeffrey Conn, Jerri M. Rook
Nonselective
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, antimuscarinic 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 antiparkinsonian
and antidystonic efficacy observed with the use of nonselective antimuscarinic
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 nonselective antimuscarinic therapeutics
and may decrease or eliminate the adverse effects associated with
these drugs. However, this has not been directly tested due to lack
of selective antagonists of M4. Here, we utilize genetic
mAChR knockout animals in combination with nonselective mAChR antagonists
to confirm that the M4 receptor activation is required
for the locomotor-stimulating and antiparkinsonian efficacy in rodent
models. We also report the synthesis, discovery, and characterization
of the first-in-class selective M4 antagonists VU6013720,
VU6021302, and VU6021625 and confirm that these optimized compounds
have antiparkinsonian and antidystonic efficacy in pharmacological
and genetic models of movement disorders.