Sign Inversion in Photopharmacology: Incorporation of Cyclic Azobenzenes in Photoswitchable Potassium Channel Blockers and Openers

Photopharmacology relies on ligands that change their pharmacodynamics upon photoisomerization. Many of these ligands are azobenzenes that are thermodynamically more stable in their elongated <i>trans</i>configuration, which predominates in the dark. Often, they are biologically active in this form and lose activity upon irradiation and photoisomerization to their <i>cis</i>-isomer. Recently, cyclic azobenzenes, so-called diazocines, have emerged. They are thermodynamically more stable in their bent <i>cis</i>­‑form than in their elongated <i>trans</i>-form. Incorporation of these switches into a variety of photopharmaceuticals could convert dark-active ligands into dark-inactive ligands, which is preferred in most biological applications. This “pharmacological sign-inversion” is demonstrated for a photochromic blocker of voltage-gated potassium channels, termed <b>CAL</b>, and a photochromic opener of G-protein-coupled inwardly rectifying potassium (GIRK) channels, termed <b>CLOGO</b>.<br>