Hybrid Allosteric Modulators of M1 Muscarinic Receptors Enhance Acetylcholine Efficacy and Decrease Locomotor Activity and Turning Behaviors in Zebrafish.

Autor: Widman CJ; University of Toledo., Ventresca S; University of Toledo., Dietrich J; University of Toledo., Elmslie G; Penn State University., Smith H; University of Toledo., Kaup G; University of Toledo., Wesley A; University of Toledo., Doenecke M; University of Toledo., Williams FE; University of Toledo., Schiefer IT; University of Toledo., Ellis J; Penn State University., Messer WS; University of Toledo.
Jazyk: angličtina
Zdroj: Research square [Res Sq] 2024 Feb 15. Date of Electronic Publication: 2024 Feb 15.
DOI: 10.21203/rs.3.rs-3901189/v1
Abstrakt: Allosteric modulation of muscarinic acetylcholine receptors (mAChR) has been identified as a potential strategy for regulating cholinergic signaling in the treatment of various neurological disorders. Most positive allosteric modulators (PAMs) of mAChR enhance agonist affinity and potency, while very few PAMs selectively enhance G-protein coupling efficacy (e.g., amiodarone). The key structural features of amiodarone responsible for enhancement of mAChR efficacy were examined in CHO cells expressing M 1 receptors. Subsequent incorporation of these structural features into previously identified allosteric modulators of potency (i.e., n-benzyl isatins) generated hybrid ligands that demonstrated similar or better enhancement of mAChR efficacy, lower in vivo toxicity, and higher allosteric binding affinity relative to amiodarone. Notable hybrid ligands include 8a and 8b which respectively demonstrated the strongest binding affinity and the most robust enhancement of mAChR efficacy as calculated from an allosteric operational model. Amiodarone derivatives and hybrid ligands were additionally screened in wildtype zebrafish ( Danio rerio ) to provide preliminary in vivo toxicity data as well as to observe effects on locomotor and turning behaviors relative to other mAChR PAMs. Several compounds, including 8a and 8c , reduced locomotor activity and increased measures of turning behaviors in zebrafish, suggesting that allosteric modulation of muscarinic receptor efficacy might be useful in the treatment of repetitive behaviors associated with autism spectrum disorder (ASD) and other neuropsychiatric disorders.
Competing Interests: Additional Declarations: Competing interest reported. WSM holds patents for the use of muscarinic agonists in the treatment of neurological disorders and is the founder and president of Psyneurgy Pharmaceuticals LLC. WSM, ITS, CJW, HS, GK, and JE have submitted a patent application covering the use of allosteric modulators of muscarinic receptors in the treatment of neurological disorders.
Databáze: MEDLINE
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