Researchers at the Paul Scherrer Institute PSI have observed for the first time at the molecular level how a light-switchable active ingredient against high blood pressure changes its shape and thus controls its effect on the receptor. Using ultrafast measurements at the X-ray free-electron laser SwissFEL, they were able to show why the molecule photoazolol-1 increases or decreases its blood pressure-lowering power depending on light irradiation. The results pave the way for drugs that can be activated in a targeted manner with light in just one part of the body, thus avoiding side effects in other organs.

The beta-blocker studied is based on a conventional substance that has been used for decades to treat high blood pressure and cardiac arrhythmias. Through a built-in azobenzene group, the molecule flips over from a straight to a curved shape under violet light – within picoseconds. In its straight form, it fits perfectly into the binding pocket of certain β-adrenergic receptors and actively blocks them. In the curved form, it gets stuck in the pocket, but inhibits the receptor to a lesser extent. The active ingredient then acts rather passively, without completely releasing the docking site for stress hormones such as adrenaline.

This means that the light switch not only functions as a simple on-off system, but also as a finely adjustable dimmer. With green light, the curved shape can be quickly transformed back into the straight one. Cell experiments had already shown that it can be used to control the beat rate of heart muscle cells. The PSI measurements now provide the atomic explanation for this.

The study, which has been published in the journal “Angewandte Chemie”, was carried out in collaboration with researchers from the Consejo Superior de Investigaciones Científicas in Barcelona and the PSI spin-off company leadXPro. In the future, the results should help to develop further light-switchable active ingredients in a more targeted manner – for example against autoimmune diseases or Parkinson’s disease.

Editor: X-Press Journalistenbüro GbR

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