Neue Ziele für die Photopharmakologie

Abstract

Das Feld der Photopharmakologie nutzt durch Licht schaltbare Moleküle, um Kontrolle über die Wirkung biologisch aktiver Verbindungen zu erlangen. Das Ziel ist es, die systemische Toxizität von Wirkstoffen wie auch die Herausbildung von Resistenzen zu vermindern und gleichzeitig eine extrem hohe Präzision in der Behandlung zu erreichen. Durch die Verwendung niedermolekularer Verbindungen stellt die Photopharmakologie eine valide Alternative zur Optogenetik dar. Wir präsentieren hier einen Überblick über die pharmakologischen Zielstrukturen in verschiedenen Organen sowie über Organsysteme im menschlichen Körper, die auf nicht‐invasive Weise angesteuert werden können. Wir diskutieren die Perspektiven einer selektiven Lichtzuführung zu diesen Organen sowie die spezifischen Anforderungen lichtaktivierbarer Wirkstoffe. Über anwendungsorientierte Aspekte hinaus sind wir bestrebt, die Wirkstofftauglichkeit (“druggability”) pharmazeutischer Zielstrukturen anhand aktueller Ergebnisse zu illustrieren. Ferner wollen wir aufzeigen, an welchen Stellen neue Ansätze erforscht werden müssen, damit die Umsetzung von “intelligentem” Moleküldesign in der Photopharmakologie zur klinischen Anwendung gelingt.

The Art of Building Small: From Molecular Switches to Motors (Nobel Lecture)

“…[48] Using such principles we have designed potent photoswitchable mast cell inhibitors [49] while other groups have reported photoswitchable nociception, human carbonic anhydrase inhibition, cell division and control of neural processes among others demonstrating the broad scope and potential of photopharmacology. [42,43,50] A next step in addressing future challenges and arriving at more effective medical therapies might be the design of more complex responsive systems in which sensing,t ransport and delivery and therapeutic action are combined and with multiple functions that can be addressed orthogonally with external stimuli. Recently,w eh ave taken the first steps towards highly selective orthogonal control in multifunctional systems using photocleavable or photoswitchable groups.…”

“…[51] It should be emphasized that there are ample opportunities to combine photochemical switches with various other switching functions.T he non-invasive up-and down-regulation of competitive chemical and biological pathways in complex (bio-)molecular networks will open fascinating opportunities in chemical biology and the study of dynamic molecular systems. [50]…”

Targeted optical fluorescence imaging: a meta-narrative review and future perspectives

“…This will support the set-up of guidelines for appropriate use Combining optoacoustic imaging and targeted tracers Investigate the options regarding application of optoacoustic imaging in combination with available targeted tracers for increasing the signal and more specific imaging [56] Therapeutic fluorophore development Designing and validating new fluorophores with properties suitable for medical purposes, e.g. appropriate size, positive effects on targeting agents and beneficial pharmacokinetic properties [113] Combination with light-activated therapeutics Focus on development of light-controlled therapeutic modalities, such as photodynamic therapy and photo pharmacology, and their combination with optical fluorescence imaging as a theranostic modality [124] Multimodal tracer development Design, synthesis and evaluation of multimodal tracers that allow combination of optical fluorescence imaging with other imaging techniques (PET/CT, SPECT, MRI, CT and ultrasound). This offers the opportunity of combined pre-operative and intraoperative imaging.…”

Development of an Indole-Amide-Based Photoswitchable Cannabinoid Receptor Subtype 1 (CB1R) “Cis-On” Agonist

“…In this way, although it is possible to activate the receptor in a precise temporal–spatial way, it is not possible to return to the initial state spontaneously. To solve this, new ligands have been designed, which can function as molecular switches in such a way that they can activate or deactivate the receptor through the use of external light sources . When irradiated at specific wavelengths, these photo-ligands can isomerize in such a way that they can go from an inactivated “off” form to an active “on” photoisomer, generating precise time control of the biological activity of the receptor. − …”