Lecture
Photopharmacology - spatiotemporal control of native receptors in vivo with photoactive molecule
- Date
- Wednesday 7 December 2022
- Time
- Location
-
Gorlaeus Building
Einsteinweg 55
2333 CC Leiden - Room
- DM1.09
Abstract
The administration of a photocontrolled ligand in combination with illumination that is patterned in space and time can provide a novel degree of control and regulation of receptor activity. This method would allow precisely focusing the action of the ligand controlling the location and the temporal extension of its effects. When applied in vivo, the use of photoregulation can reduce side effects by targeting receptors located in focused tissues, establishing personalized drug schedules to patient needs.
We have recently developed light-regulated negative allosteric modulators for metabotropic glutamate receptors (mGluRs). These include Alloswitch-1 [1] and related phenylazopyridines with NAM activity in mGlu5 and OptoGluNAM4.1, the first mGlu4 NAM active in vivo [2]. These photopharmacological tools are based in photoswitchable azobenzene scaffolds that serve for the real-time control of the receptors in cell assays. The molecules show a robust activity dependent of the illumination conditions allowing the real-time regulation of the intracellular effects of these GPCRs. [3]
Moreover, when the molecules are applied in vivo and combined with external or internal light sources, we can register interesting light dependent behavioral effects in zebra fish embryos, tadpoles and rodents, including some pain models. We have shown that localized (in)activation with light of a specific area in the amygdala of live mice results in a control of chronic pain. [4] The key experiment for this uses a mGlu4 photoswitchable azobenzene ligand to control activity of endogenous receptors in vivo with light. With this molecule, we rapidly and reversibly inhibited chronic pain behavioral symptoms after illumination in the amygdala of rodent brain while measuring the painful response in the periphery.
We have also developed molecules for the photocontrol of adrenergic receptors, [5] and a derivative to release locally morphine in vivo to control pain avoiding opioid side-effects. [6]
Photopharmacology approaches are effective to study the dynamic response of localized receptors and show potential for spatiotemporal regulation of drugs.
References
- Pittolo et al (2014) Nat Chem Biol.10:813-5.
- Rovira et al Cell Chem Biol. 23):929-34
- Gómez-Santacana et al ACS Cent Sci (2016 ) Dec 19, DOI:10.1021/acscentsci.6b00353
- Zussy C, et al. Mol Psychiatry. (2016) Dec 20. doi: 10.1038/mp.2016.223.
- Duran-Corbella et al, Angew Chem Int Ed Engl. 2022 Jul 25;61(30):e202203449. doi: 10.1002/anie.202203449.
- Lopez-Cano et al Br J Pharmacol. 2021 Aug 6. doi: 10.1111/bph.15645.