Synthesis and Pharmacological Characterization of New Photocaged Agonists for Histamine H 3 and H 4 Receptors.

The modulation of biological processes with light-sensitive chemical probes promises precise temporal and spatial control. Yet, the design and synthesis of suitable probes is a challenge for medicinal chemists. This article introduces a photocaging strategy designed to modulate the pharmacology of histamine H3 receptors (H3 R) and H4 receptors (H4 R). Employing the photoremovable group BODIPY as the caging entity for two agonist scaffolds-immepip and 4-methylhistamine-for H3 R and H4 R, respectively, we synthesized two BODIPY-caged compounds, 5 (VUF25657) and 6 (VUF25678), demonstrating 10-100-fold reduction in affinity for their respective receptors. Notably, the caged H3 R agonist, VUF25657, exhibits approximately a 100-fold reduction in functional activity. The photo-uncaging of VUF25657 at 560 nm resulted in the release of immepip, thereby restoring binding affinity and potency in functional assays. This approach presents a promising method to achieve optical control of H3 R receptor pharmacology.