Department of Chemistry and Center for Integrated Protein Science (CIPSM), Ludwig Maximilian University Munich, Butenandtstr. 5-13, 81377, Munich, Germany.
Center for DNA Nanotechnology, Department of Chemistry and iNANO, Aarhus University, Gustav Wieds Vej 14, 8000, Aarhus C, Denmark.
Angew Chem Int Ed Engl. 2019 Oct 21;58(43):15421-15428. doi: 10.1002/anie.201905790. Epub 2019 Sep 12.
Photopharmacology relies on ligands that change their pharmacodynamics upon photoisomerization. Many of these ligands are azobenzenes that are thermodynamically more stable in their elongated trans-configuration. Often, they are biologically active in this form and lose activity upon irradiation and photoisomerization to their cis-isomer. Recently, cyclic azobenzenes, so-called diazocines, have emerged, which are thermodynamically more stable in their bent cis-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 CAL, and a photochromic opener of G protein-coupled inwardly rectifying potassium (GIRK) channels, termed CLOGO.
光药理学依赖于那些在光异构化时改变其药效动力学的配体。这些配体中有许多是偶氮苯，它们在拉长的反式构象中热力学更稳定。通常情况下，它们在这种形式下具有生物活性，并且在照射和光异构化为顺式异构体时失去活性。最近，出现了所谓的二氮嗪的环状偶氮苯，它们在弯曲的顺式构象中热力学更稳定。将这些开关整合到各种光药物中，可以将暗活性配体转化为暗非活性配体，这在大多数生物应用中是首选的。这种“药理学反转”在一种称为 CAL 的电压门控钾通道光致变色阻断剂和一种称为 CLOGO 的 G 蛋白偶联内向整流钾 (GIRK) 通道光致变色开放剂中得到了证明。
