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

ABSTRACT: 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 M₁ 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 high

SUBMITTER: Widman CJ 

PROVIDER: S-EPMC10896388 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature