Low-basicity 5-HT₇ Receptor Agonists Synthesized Using the van Leusen Multicomponent Protocol

Area of Science:

• Medicinal Chemistry
• Neuroscience
• Pharmacology

Background:

• The 5-HT7 receptor is implicated in various central nervous system (CNS) functions and disorders.
• Developing selective ligands for the 5-HT7 receptor is challenging due to its structural similarity to other serotonin receptors.
• Low-basicity scaffolds with high affinity and agonist function for the 5-HT7 receptor are needed.

Purpose of the Study:

• To synthesize and characterize novel 5-aryl-1-alkylimidazole derivatives as potential 5-HT7 receptor agonists.
• To evaluate the affinity, selectivity, metabolic stability, and in vivo efficacy of these compounds.
• To elucidate the binding mode and structure-activity relationships (SAR) for 5-HT7 receptor interaction.

Main Methods:

• Synthesis of imidazole derivatives via the van Leusen multicomponent reaction.
• In vitro assays to determine binding affinity (Ki) and functional activity (EC50) for 5-HT7 and related receptors.
• Cell-based assays (HEK-293, HepG2) to assess metabolic stability and toxicity.
• In vivo pharmacokinetic studies in mice, including blood-brain barrier penetration.
• Behavioral testing (novel object recognition) in mice to evaluate cognitive effects.
• Molecular docking studies to predict binding modes and interactions with the 5-HT7 receptor.

Main Results:

• A series of 5-aryl-1-alkylimidazole derivatives were successfully synthesized.
• Lead compounds AGH-107 (1o) and 1e demonstrated high affinity (Ki = 6 nM and 30 nM, respectively) and agonist function at the 5-HT7 receptor.
• Compounds exhibited high selectivity over 5-HT1A and other CNS targets (e.g., 176-fold for 1o over 5-HT1A).
• AGH-107 showed rapid absorption, high blood-brain barrier penetration, and significant brain concentration after intraperitoneal administration in mice.
• AGH-107 demonstrated in vivo activity in the novel object recognition test.
• Docking studies and SAR analysis indicated the importance of halogen bonding for potent derivatives and high selectivity.

Conclusions:

• The synthesized imidazole derivatives represent a novel chemotype of low-basicity 5-HT7 receptor agonists.
• The lead compounds possess favorable pharmacokinetic properties, including brain penetration and metabolic stability.
• These findings support the potential of these compounds as therapeutic agents for CNS disorders modulated by the 5-HT7 receptor.