Allosteric modulators of M₁ muscarinic receptors enhance acetylcholine efficacy and decrease locomotor activity and...

Area of Science:

• Neuroscience
• Pharmacology

Background:

• Allosteric modulation of muscarinic acetylcholine receptors (mAChR) is a key strategy for neurological disorder treatment.
• Most positive allosteric modulators (PAMs) enhance agonist affinity, but few enhance G protein coupling efficacy.

Purpose of the Study:

• To identify structural features of amiodarone that enhance mAChR efficacy.
• To develop novel mAChR PAMs with improved efficacy, safety, and binding affinity.

Main Methods:

• Examined amiodarone's structural features in CHO cells expressing M1 receptors.
• Incorporated these features into n-benzyl isatins to create hybrid ligands.
• Screened compounds in zebrafish for in vivo toxicity and behavioral effects.

Main Results:

• Novel ligands demonstrated enhanced mAChR efficacy, lower toxicity, and higher binding affinity than amiodarone.
• Compounds 8a and 8c showed the strongest binding affinity and efficacy, respectively.
• Zebrafish studies indicated reduced locomotor activity and increased turning behaviors with select compounds.

Conclusions:

• Allosteric modulation of mAChR efficacy offers a potential therapeutic approach for neuropsychiatric disorders, including autism spectrum disorder (ASD).
• Hybrid ligands combining amiodarone's efficacy-enhancing features with n-benzyl isatins represent a promising class of mAChR modulators.