In Vivo Determination of Muscarinic Acetylcholine Receptor Availability in Schizophrenia

Drugs that treat chronic obstructive pulmonary disease by antagonizing the M3 muscarinic acetylcholine receptor (M3R) have had a significant effect on health, but can suffer from their lack of selectivity against the M2R subtype, which modulates heart rate. Beginning with the crystal structures of M2R and M3R, we exploited a single amino acid difference in their orthosteric binding pockets using molecular docking and structure-based design. The resulting M3R antagonists had up to 100-fold selectivity over M2R in affinity and over 1,000-fold selectivity in vivo. The crystal structure of the M3R-selective antagonist in complex with M3R corresponded closely to the docking-predicted geometry, providing a template for further optimization.

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Muscarinic acetylcholine receptor regulates self-renewal of early erythroid progenitors

Science Translational Medicine ◽

10.1126/scitranslmed.aaw3781 ◽

2019 ◽

Vol 11 (511) ◽

pp. eaaw3781 ◽

Cited By ~ 1

Author(s):

Gaurang Trivedi ◽

Daichi Inoue ◽

Cynthia Chen ◽

Lillian Bitner ◽

Young Rock Chung ◽

...

Keyword(s):

Acetylcholine Receptor ◽

Muscarinic Acetylcholine Receptor ◽

Cholinergic Receptor ◽

Erythroid Cell ◽

Erythroid Progenitors ◽

Receptor Antagonists ◽

Erythroid Progenitor ◽

Self Renewal ◽

Muscarinic Acetylcholine

Adult stem and progenitor cells are uniquely capable of self-renewal, and targeting this process represents a potential therapeutic opportunity. The early erythroid progenitor, burst-forming unit erythroid (BFU-E), has substantial self-renewal potential and serves as a key cell type for the treatment of anemias. However, our understanding of mechanisms underlying BFU-E self-renewal is extremely limited. Here, we found that the muscarinic acetylcholine receptor, cholinergic receptor, muscarinic 4 (CHRM4), pathway regulates BFU-E self-renewal and that pharmacological inhibition of CHRM4 corrects anemias of myelodysplastic syndrome (MDS), aging, and hemolysis. Genetic down-regulation of CHRM4 or pharmacologic inhibition of CHRM4 using the selective antagonist PD102807 promoted BFU-E self-renewal, whereas deletion ofChrm4increased erythroid cell production under stress conditions in vivo. Moreover, muscarinic acetylcholine receptor antagonists corrected anemias in mouse models of MDS, aging, and hemolysis in vivo, extending the survival of mice with MDS relative to that of controls. The effects of muscarinic receptor antagonism on promoting expansion of BFU-Es were mediated by cyclic AMP induction of the transcription factor CREB, whose targets up-regulated key regulators of BFU-E self-renewal. On the basis of these data, we propose a model of hematopoietic progenitor self-renewal through a cholinergic-mediated “hematopoietic reflex” and identify muscarinic acetylcholine receptor antagonists as potential therapies for anemias associated with MDS, aging, and hemolysis.

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In vivo regulation of muscarinic acetylcholine receptor number and function in embryonic chick heart.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(18)43370-4 ◽

1981 ◽

Vol 256 (15) ◽

pp. 7941-7948 ◽

Cited By ~ 7

Author(s):

S.W. Halvorsen ◽

N.M. Nathanson

Keyword(s):

Acetylcholine Receptor ◽

Muscarinic Acetylcholine Receptor ◽

Embryonic Chick ◽

Muscarinic Acetylcholine ◽

Chick Heart ◽

Embryonic Chick Heart ◽

Receptor Number ◽

And Function

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Discovery of the first selective M4 muscarinic acetylcholine receptor antagonists with in vivo anti-parkinsonian and anti-dystonic efficacy

10.1101/2020.10.12.324152 ◽

2020 ◽

Author(s):

Mark S. Moehle ◽

Aaron M. Bender ◽

Jonathan W. Dickerson ◽

Daniel J. Foster ◽

Yuping Donsante ◽

...

Keyword(s):

Adverse Effects ◽

Acetylcholine Receptor ◽

Movement Disorders ◽

Intracellular Signaling ◽

Acetylcholine Receptors ◽

Muscarinic Acetylcholine Receptor ◽

Muscarinic Acetylcholine Receptors ◽

Muscarinic Acetylcholine ◽

Selective Antagonists

AbstractNon-selective antagonists of muscarinic acetylcholine receptors (mAChRs) that broadly inhibit all five mAChR subtypes provide an efficacious treatment for some movement disorders, including Parkinson 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 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 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 the first-in-class selective M4 antagonists VU6013720, VU6021302, and VU6021625 and confirm that these optimized compounds have anti-parkinsonian and anti-dystonic efficacy in pharmacological and genetic models of movement disorders.

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