Discovery, Optimization, and Biological Characterization of 2,3,6-Trisubstituted Pyridine-Containing M₄ Positive...

Area of Science:

• Medicinal Chemistry
• Neuroscience
• Pharmacology

Background:

• Muscarinic acetylcholine receptor 4 (M₄) is a G protein-coupled receptor implicated in various neurological disorders.
• Positive allosteric modulators (PAMs) offer a potential therapeutic strategy by enhancing receptor function in a subtype-selective manner.
• Developing selective M₄ PAMs with favorable pharmacokinetic and safety profiles remains a significant challenge.

Purpose of the Study:

• To discover and optimize novel 2,3-disubstituted and 2,3,6-trisubstituted M₄ PAMs.
• To identify a potent, selective, brain-penetrant M₄ PAM tool compound for preclinical studies.
• To evaluate the efficacy and safety profile of the optimized M₄ PAM in animal models.

Main Methods:

• Iterative library synthesis and structure-activity relationship (SAR) studies to identify key structural features for potency and selectivity.
• In vitro assays to characterize receptor binding and functional activity.
• In vivo preclinical models, including amphetamine-induced hyperlocomotion in rats and mice, to assess antipsychotic-like efficacy.
• Pharmacokinetic and safety assessments, including evaluation of cholinergic-related adverse effects.

Main Results:

• Discovery of a new series of M₄ PAMs with potent activity.
• Identification of compound 24, a selective, brain-penetrant M₄ PAM.
• Compound 24 demonstrated dose-dependent efficacy in reversing amphetamine-induced hyperlocomotion in M₄-expressing rodents, an effect absent in M₄ knockout mice.
• Compound 24 exhibited a potentially improved safety profile with fewer and less severe cholinergic adverse effects compared to the nonselective M₄ agonist xanomeline.

Conclusions:

• The identified M₄ PAMs, particularly compound 24, represent promising candidates for further development.
• Selective M₄ PAMs hold potential for treating neuropsychiatric disorders with an improved safety margin.
• Compound 24 serves as a valuable tool compound for investigating M₄ receptor function in vivo.