Synthesis and Characterization of a Bidirectional Photoswitchable Antagonist Toolbox for Real-Time GPCR Photopharmacology.

Autor:	Hauwert NJ; Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, Faculty of Science , Vrije Universiteit Amsterdam , De Boelelaan 1108 , 1081 HZ Amsterdam , The Netherlands., Mocking TAM; Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, Faculty of Science , Vrije Universiteit Amsterdam , De Boelelaan 1108 , 1081 HZ Amsterdam , The Netherlands., Da Costa Pereira D; Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, Faculty of Science , Vrije Universiteit Amsterdam , De Boelelaan 1108 , 1081 HZ Amsterdam , The Netherlands., Kooistra AJ; Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, Faculty of Science , Vrije Universiteit Amsterdam , De Boelelaan 1108 , 1081 HZ Amsterdam , The Netherlands., Wijnen LM; Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, Faculty of Science , Vrije Universiteit Amsterdam , De Boelelaan 1108 , 1081 HZ Amsterdam , The Netherlands., Vreeker GCM; Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, Faculty of Science , Vrije Universiteit Amsterdam , De Boelelaan 1108 , 1081 HZ Amsterdam , The Netherlands., Verweij EWE; Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, Faculty of Science , Vrije Universiteit Amsterdam , De Boelelaan 1108 , 1081 HZ Amsterdam , The Netherlands., De Boer AH; Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, Faculty of Science , Vrije Universiteit Amsterdam , De Boelelaan 1108 , 1081 HZ Amsterdam , The Netherlands., Smit MJ; Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, Faculty of Science , Vrije Universiteit Amsterdam , De Boelelaan 1108 , 1081 HZ Amsterdam , The Netherlands., De Graaf C; Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, Faculty of Science , Vrije Universiteit Amsterdam , De Boelelaan 1108 , 1081 HZ Amsterdam , The Netherlands., Vischer HF; Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, Faculty of Science , Vrije Universiteit Amsterdam , De Boelelaan 1108 , 1081 HZ Amsterdam , The Netherlands., de Esch IJP; Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, Faculty of Science , Vrije Universiteit Amsterdam , De Boelelaan 1108 , 1081 HZ Amsterdam , The Netherlands., Wijtmans M; Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, Faculty of Science , Vrije Universiteit Amsterdam , De Boelelaan 1108 , 1081 HZ Amsterdam , The Netherlands., Leurs R; Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, Faculty of Science , Vrije Universiteit Amsterdam , De Boelelaan 1108 , 1081 HZ Amsterdam , The Netherlands.
Jazyk:	angličtina
Zdroj:	Journal of the American Chemical Society [J Am Chem Soc] 2018 Mar 28; Vol. 140 (12), pp. 4232-4243. Date of Electronic Publication: 2018 Mar 14.
DOI:	10.1021/jacs.7b11422
Abstrakt:	Noninvasive methods to modulate G protein-coupled receptors (GPCRs) with temporal and spatial precision are in great demand. Photopharmacology uses photons to control in situ the biological properties of photoswitchable small-molecule ligands, which bodes well for chemical biological precision approaches. Integrating the light-switchable configurational properties of an azobenzene into the ligand core, we developed a bidirectional antagonist toolbox for an archetypical family A GPCR, the histamine H 3 receptor (H 3 R). From 16 newly synthesized photoswitchable compounds, VUF14738 (28) and VUF14862 (33) were selected as they swiftly and reversibly photoisomerize and show over 10-fold increased or decreased H 3 R binding affinities, respectively, upon illumination at 360 nm. Both ligands combine long thermal half-lives with fast and high photochemical trans-/ cis conversion, allowing their use in real-time electrophysiology experiments with oocytes to confirm dynamic photomodulation of H 3 R activation in repeated second-scale cycles. VUF14738 and VUF14862 are robust and fatigue-resistant photoswitchable GPCR antagonists suitable for spatiotemporal studies of H 3 R signaling.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu