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Development of an indole-amide-based photoswitchable cannabinoid receptor subtype 1 (CB1R) 'Cis-On' Agonist

(2022) ACS CHEMICAL NEUROSCIENCE. 13(16). p.2410-2435
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Abstract
Activation of the human cannabinoid receptor type 1 (hCB(1)R) 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 hCB(1)R, 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 (K-i (cis-form) = 0.18 mu M), with a marked difference in affinity with respect to its inactive "trans-off" form (CB1R K-i 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 beta arr2 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 hCB(1)R in disorders associated with the endocannabinoid system.
Keywords
Cell Biology, Cognitive Neuroscience, Physiology, Biochemistry, General Medicine, photopharmacology, CB1 agonist, G-protein-coupled receptor, diazocine, photorimonabant, optical control, SYNTHETIC CANNABINOIDS, IONIZABLE GROUPS, OPTICAL CONTROL, CB2, PERFORMANCE, DERIVATIVES, ACTIVATION, ENERGIES, DESIGN, SYSTEM

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Citation

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MLA
Rodríguez-Soacha, Diego A., et al. “Development of an Indole-Amide-Based Photoswitchable Cannabinoid Receptor Subtype 1 (CB1R) ‘Cis-On’ Agonist.” ACS CHEMICAL NEUROSCIENCE, vol. 13, no. 16, 2022, pp. 2410–35, doi:10.1021/acschemneuro.2c00160.
APA
Rodríguez-Soacha, D. A., Steinmüller, S. A. M., Işbilir, A., Fender, J., Deventer, M., Ramírez, Y. A., … Decker, M. (2022). Development of an indole-amide-based photoswitchable cannabinoid receptor subtype 1 (CB1R) “Cis-On” Agonist. ACS CHEMICAL NEUROSCIENCE, 13(16), 2410–2435. https://doi.org/10.1021/acschemneuro.2c00160
Chicago author-date
Rodríguez-Soacha, Diego A., Sophie A. M. Steinmüller, Ali Işbilir, Julia Fender, Marie Deventer, Yesid A. Ramírez, Anna Tutov, et al. 2022. “Development of an Indole-Amide-Based Photoswitchable Cannabinoid Receptor Subtype 1 (CB1R) ‘Cis-On’ Agonist.” ACS CHEMICAL NEUROSCIENCE 13 (16): 2410–35. https://doi.org/10.1021/acschemneuro.2c00160.
Chicago author-date (all authors)
Rodríguez-Soacha, Diego A., Sophie A. M. Steinmüller, Ali Işbilir, Julia Fender, Marie Deventer, Yesid A. Ramírez, Anna Tutov, Christoph Sotriffer, Christophe Stove, Kristina Lorenz, Martin J. Lohse, James N. Hislop, and Michael Decker. 2022. “Development of an Indole-Amide-Based Photoswitchable Cannabinoid Receptor Subtype 1 (CB1R) ‘Cis-On’ Agonist.” ACS CHEMICAL NEUROSCIENCE 13 (16): 2410–2435. doi:10.1021/acschemneuro.2c00160.
Vancouver
1.
Rodríguez-Soacha DA, Steinmüller SAM, Işbilir A, Fender J, Deventer M, Ramírez YA, et al. Development of an indole-amide-based photoswitchable cannabinoid receptor subtype 1 (CB1R) “Cis-On” Agonist. ACS CHEMICAL NEUROSCIENCE. 2022;13(16):2410–35.
IEEE
[1]
D. A. Rodríguez-Soacha et al., “Development of an indole-amide-based photoswitchable cannabinoid receptor subtype 1 (CB1R) ‘Cis-On’ Agonist,” ACS CHEMICAL NEUROSCIENCE, vol. 13, no. 16, pp. 2410–2435, 2022.
@article{01GQ75TENBXG8C28N69XVMT4DM,
  abstract     = {{Activation of the human cannabinoid receptor type 1 (hCB(1)R) 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 hCB(1)R, 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 (K-i (cis-form) = 0.18 mu M), with a marked difference in affinity with respect to its inactive "trans-off" form (CB1R K-i 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 beta arr2 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 hCB(1)R in disorders associated with the endocannabinoid system.}},
  author       = {{Rodríguez-Soacha, Diego A. and Steinmüller, Sophie A. M. and Işbilir, Ali and Fender, Julia and Deventer, Marie and Ramírez, Yesid A. and Tutov, Anna and Sotriffer, Christoph and Stove, Christophe and Lorenz, Kristina and Lohse, Martin J. and Hislop, James N. and Decker, Michael}},
  issn         = {{1948-7193}},
  journal      = {{ACS CHEMICAL NEUROSCIENCE}},
  keywords     = {{Cell Biology,Cognitive Neuroscience,Physiology,Biochemistry,General Medicine,photopharmacology,CB1 agonist,G-protein-coupled receptor,diazocine,photorimonabant,optical control,SYNTHETIC CANNABINOIDS,IONIZABLE GROUPS,OPTICAL CONTROL,CB2,PERFORMANCE,DERIVATIVES,ACTIVATION,ENERGIES,DESIGN,SYSTEM}},
  language     = {{eng}},
  number       = {{16}},
  pages        = {{2410--2435}},
  title        = {{Development of an indole-amide-based photoswitchable cannabinoid receptor subtype 1 (CB1R) 'Cis-On' Agonist}},
  url          = {{http://doi.org/10.1021/acschemneuro.2c00160}},
  volume       = {{13}},
  year         = {{2022}},
}

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