2. Academic Validation
  3. Development of an Indole-Amide-Based Photoswitchable Cannabinoid Receptor Subtype 1 (CB1R) "Cis-On" Agonist

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

  • ACS Chem Neurosci. 2022 Aug 17;13(16):2410-2435. doi: 10.1021/acschemneuro.2c00160.
Diego A Rodríguez-Soacha 1,  Sophie A M Steinmüller 1,  Ali Işbilir 2 3,  Julia Fender 2,  Marie H Deventer 4,  Yesid A Ramírez 1 5,  Anna Tutov 1,  Christoph Sotriffer 1,  Christophe P Stove 4,  Kristina Lorenz 2 6,  Martin J Lohse 2 3 7,  James N Hislop 8,  Michael Decker 1
Affiliations

Affiliations

  • 1 Pharmazeutische und Medizinische Chemie, Institut für Pharmazie und Lebensmittelchemie, Julius-Maximilians-Universität Würzburg, Am Hubland, 97074 Würzburg, Germany.
  • 2 Institut für Pharmakologie und Toxikologie, Julius-Maximilians-Universität Würzburg, Versbacher Str. 9, D-97078 Würzburg, Germany.
  • 3 Receptor Signaling Group, Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
  • 4 Laboratory of Toxicology, Department of Bioanalysis, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium.
  • 5 Departamento de Ciencias Farmacéuticas, Facultad de Ciencias Naturales, Universidad Icesi, Valle del Cauca, 760031 Cali, Colombia.
  • 6 Leibniz-Institut für Analytische Wissenschaften─ISAS e.V., Bunsen-Kirchhoff-Str. 11, 44139 Dortmund, Germany.
  • 7 ISAR Bioscience Institut, 82152 Planegg/Munich, Germany.
  • 8 School of Medicine, Medical Sciences and Nutrition, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, United Kingdom.
PMID: 35881914 DOI: 10.1021/acschemneuro.2c00160
Abstract

Activation of the human Cannabinoid Receptor type 1 (hCB1R) with high spatiotemporal control is useful to study processes involved in different pathologies related to nociception, metabolic alterations, and neurological disorders. To synthesize new agonist ligands for hCB1R, we have designed different classes of photoswitchable molecules based on an indole core. The modifications made to the central core have allowed us to understand the molecular characteristics necessary to design an agonist with optimal pharmacological properties. Compound 27a shows high affinity for CB1R (Ki (cis-form) = 0.18 μM), with a marked difference in affinity with respect to its inactive "trans-off" form (CB1R Ki trans/cis ratio = 5.4). The novel compounds were evaluated by radioligand binding studies, receptor internalization, sensor receptor activation (GRABeCB2.0), Western blots for analysis of ERK1/2 activation, NanoBiT βarr2 recruitment, and calcium mobilization assays, respectively. The data show that the novel agonist 27a is a candidate for studying the optical modulation of cannabinoid receptors (CBRs), serving as a new molecular tool for investigating the involvement of hCB1R in disorders associated with the endocannabinoid system.

Keywords

CB1 agonist; G-protein-coupled receptor; diazocine; optical control; photopharmacology; photorimonabant.

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