Entwicklung photochromer Cannabinoid-Rezeptor-Liganden zur Untersuchung der Aktivierung und Funktion G-Protein-gekoppelter Rezeptoren
Zusammenfassung der Projektergebnisse
In the course of this project, we have developed photoswitchable ligands for both the human cannabinoid receptor subtype 1 and subtype 2 (hCB1R and hCB2R) to provide molecular probes, (pharmacological tool compounds) to investigate their receptor pharmacology. hCB1R stimulation leads to psychotropic effects upon activation by an agonist (the well-known cannabis effect), and has antiobesity effects upon blockade by an antagonist. We were able to obtain - based on the (former) antiobesity drug rimonabant - “photo-rimonabant”, which shows practically the same properties as rimonabant, but is >15fold more active in the light-activated (cis-)form. Furthermore, we also developed an agonist with higher potency in its cis-photoform. The second receptor subtype, the hCB2R, has great pharmacological relevance due to its anti- (neuro)inflammatory effects upon agonist stimulation. We were able to describe ligands for the hCB2R addressing both the ortho- and allosteric binding sites of the receptor (therefore termed “dualsteric”), and could - in a subsequent work - make such ligands photoswitchable. We finally developed another type of ligand, that is light-activated and only activates the β-arrestin signalling pathway, but not the G protein-coupled one. This compound represents the first class A G proteincoupled receptor (GPCR) photocontrollable ligand described to date with signal bias. To achieve this, we had used arylazobenzimidazole photoswitches as core for the novel molecules. We investigated this novel template by chemical, photophysical and quantumchemical means to make this molecular switch available for photopharmacology, since it is based on the “privileged structure” of benzimidazole, which is common in numerous biologically active molecules.
Projektbezogene Publikationen (Auswahl)
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Functionalized Cannabinoid Subtype 2 Receptor Ligands: Fluorescent, PET, Photochromic and Covalent Molecular Probes. ChemMedChem, 15(15), 1374-1389.
Basagni, Filippo; Rosini, Michela & Decker, Michael
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“Photo-Rimonabant”: Synthesis and Biological Evaluation of Novel Photoswitchable Molecules Derived from Rimonabant Lead to a Highly Selective and Nanomolar “Cis-On” CB1R Antagonist. ACS Chemical Neuroscience, 12(9), 1632-1647.
Rodríguez-Soacha, Diego A.; Fender, Julia; Ramírez, Yesid A.; Collado, Juan Antonio; Muñoz, Eduardo; Maitra, Rangan; Sotriffer, Christoph; Lorenz, Kristina & Decker, Michael
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Development of an Indole-Amide-Based Photoswitchable Cannabinoid Receptor Subtype 1 (CB1R) “Cis-On” Agonist. ACS Chemical Neuroscience, 13(16), 2410-2435.
Rodríguez-Soacha, Diego A.; Steinmüller, Sophie A. M.; Işbilir, Ali; Fender, Julia; Deventer, Marie H.; Ramírez, Yesid A.; Tutov, Anna; Sotriffer, Christoph; Stove, Christophe P.; Lorenz, Kristina; Lohse, Martin J.; Hislop, James N. & Decker, Michael
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Die Erhellung des “Bewusstseinsmoleküls”: Photomodulation des 5‐HT2A Rezeptors durch ein licht‐steuerbares N,N‐Dimethyltryptamin‐Derivat. Angewandte Chemie, 134(26).
Gerwe, Hubert; He, Feng; Pottie, Eline; Stove, Christophe & Decker, Michael
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Enlightening the “Spirit Molecule”: Photomodulation of the 5‐HT2A Receptor by a Light‐Controllable N,N‐Dimethyltryptamine Derivative. Angewandte Chemie International Edition, 61(26).
Gerwe, Hubert; He, Feng; Pottie, Eline; Stove, Christophe & Decker, Michael
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Bridging the Binding Sites 2.0: Photoswitchable Dualsteric Ligands for the Cannabinoid 2 Receptor. ACS Chemical Neuroscience, 14(20), 3737-3744.
Steinmüller, Sophie A. M.; Tutov, Anna; Hislop, James N. & Decker, Michael
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Bridging the Binding Sites: Dualsteric Ligands for the Cannabinoid 2 Receptor (CB2R). Advanced Therapeutics, 6(4).
Tutov, Anna; Steinmüller, Sophie A. M.; Ramírez, Yesid A.; Jack, Christine E.; Rodríguez‐Soacha, Diego A.; Sotriffer, Christoph; Hislop, James N. & Decker, Michael
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Mit sichtbarem Licht schaltbare Benzimidazol‐Azo‐Arene wirken als β‐Arrestin2 funktionell selektive Cannabinoid‐Rezeptor 2 Agonisten. Angewandte Chemie, 135(49).
Steinmüller, Sophie A. M.; Fender, Julia; Deventer, Marie H.; Tutov, Anna; Lorenz, Kristina; Stove, Christophe P.; Hislop, James N. & Decker, Michael
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Poster presentation and early career speaker at the 11th Adrenoceptor Symposium: Adrenoceptors and GPCR Signaling, a WCP 2023 Satellite Meeting in Glasgow, Scotland (June 2023). “Benzimidazole azo-arenes as red-shifted photoswitchable β-arrestin2-biased cannabinoid 2 receptor-selective agonists”
Sophie A. M. Steinmüller, Julia Fender, Marie H. Deventer, Anna Tutov, Christophe P. Stove, Kristina Lorenz, James N. Hislop & Michael Decker
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Visible‐Light Photoswitchable Benzimidazole Azo‐Arenes as β‐Arrestin2‐Biased Selective Cannabinoid 2 Receptor Agonists. Angewandte Chemie International Edition, 62(49).
Steinmüller, Sophie A. M.; Fender, Julia; Deventer, Marie H.; Tutov, Anna; Lorenz, Kristina; Stove, Christophe P.; Hislop, James N. & Decker, Michael
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Arylazobenzimidazoles: versatile visible-light photoswitches with tuneable Z -isomer stability. Chemical Science, 15(14), 5360-5367.
Steinmüller, Sophie A. M.; Odaybat, Magdalena; Galli, Giulia; Prischich, Davia; Fuchter, Matthew J. & Decker, Michael
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“Photo‐Adrenalines”: Photoswitchable β2‐Adrenergic Receptor Agonists as Molecular Probes for the Study of Spatiotemporal Adrenergic Signaling. Chemistry – A European Journal, 30(11).
Sink, Alexandra; Gerwe, Hubert; Hübner, Harald; Boivin‐Jahns, Valerie; Fender, Julia; Lorenz, Kristina; Gmeiner, Peter & Decker, Michael
