Bespoke library docking for 5-HT_2A receptor agonists with antidepressant activity.

Area of Science:

• Medicinal Chemistry
• Neuroscience
• Drug Discovery

Background:

• Screening ultralarge chemical libraries is crucial for ligand discovery.
• Existing efforts often overlook unexplored chemotypes, such as tetrahydropyridines.
• Tetrahydropyridines are well-suited for aminergic G-protein-coupled receptors.

Purpose of the Study:

• To investigate structure-based docking of a bespoke virtual library of tetrahydropyridines.
• To identify novel ligands for serotonin receptors, specifically 5-HT2A and 5-HT2B.
• To explore the therapeutic potential of these novel compounds.

Main Methods:

• A one-pot synthesis provided tetrahydropyridine cores with multiple derivatization sites.
• Structure-based docking of a 75-million molecule virtual library against the serotonin 5-HT2A receptor model.
• Synthesis and testing of initial molecules, followed by structure-based optimization.
• Cryo-electron microscopy for structural analysis of ligand-receptor binding.

Main Results:

• Four synthesized molecules exhibited low-micromolar activity against 5-HT2A or 5-HT2B receptors.
• Optimized compounds (R)-69 and (R)-70 showed high affinity (41 nM and 110 nM EC50) for 5-HT2A receptors.
• These agonists demonstrated unusual signaling kinetics, distinct from known psychedelic compounds.
• High brain permeability was confirmed, enabling in vivo behavioral assays.
• Compounds lacked psychedelic activity but displayed potent antidepressant effects in mouse models.

Conclusions:

• Bespoke virtual libraries can effectively sample pharmacologically relevant chemical space.
• Novel tetrahydropyridine agonists targeting serotonin receptors were discovered.
• These compounds represent a promising new class of non-psychedelic antidepressants with high brain penetration.