Allosteric modulators of M 1 muscarinic receptors enhance acetylcholine efficacy and decrease locomotor activity and turning behaviors in zebrafish.

Autor: Widman CJ; Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Mail Stop #1015, 3000 Arlington Ave., Toledo, OH, 43614, USA., Ventresca S; Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH, 43614, USA., Dietrich J; Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH, 43614, USA., Elmslie G; Departments of Psychiatry and Pharmacology, College of Medicine, Penn State University, Hershey, PA, 17033, USA., Smith H; Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Mail Stop #1015, 3000 Arlington Ave., Toledo, OH, 43614, USA., Kaup G; Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Mail Stop #1015, 3000 Arlington Ave., Toledo, OH, 43614, USA., Wesley A; Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH, 43614, USA., Doenecke M; Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH, 43614, USA., Williams FE; Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH, 43614, USA., Schiefer IT; Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Mail Stop #1015, 3000 Arlington Ave., Toledo, OH, 43614, USA.; Center for Drug Design and Development, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH, 43614, USA., Ellis J; Departments of Psychiatry and Pharmacology, College of Medicine, Penn State University, Hershey, PA, 17033, USA., Messer WS Jr; Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Mail Stop #1015, 3000 Arlington Ave., Toledo, OH, 43614, USA. william.messer@utoledo.edu.; Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH, 43614, USA. william.messer@utoledo.edu.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2024 Jun 28; Vol. 14 (1), pp. 14901. Date of Electronic Publication: 2024 Jun 28.
DOI: 10.1038/s41598-024-65445-y
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 (e.g., amiodarone) selectively enhance G protein coupling efficacy. 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 ligands that demonstrated similar or better enhancement of mAChR efficacy, lower in vivo toxicity, and higher allosteric binding affinity relative to amiodarone. Notable ligands include 8a, c 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, c, 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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