Development of Photochromic Cannabinoid Receptor Ligands to Investigate G Protein-coupled Receptor Activation and Function
Final Report Abstract
In the course of this project, we have developed photo-switchable 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 anti-obesity effects upon blockade by an antagonist. We were able to obtain - based on the (former) anti-obesity 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-photo-form. 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 photo-switchable. We finally developed another type of ligand, that is light-activated and only activates the β-arrestin signaling pathway, but not the G protein-coupled one. This compound represents the first class A G protein-coupled receptor (GPCR) photo-controllable ligand described to date with signal bias. To achieve this, we had used arylazobenzimidazole photo-switches as core for the novel molecules. We investigated this novel template by chemical, photophysical and quantum-chemical means to make this molecular switch available for photo-pharmacology, since it is based on the "privileged structure" of benzimidazole, which is common in numerous biologically active molecules.
Publications
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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
