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Development of an indole-amide-based photoswitchable cannabinoid receptor subtype 1 (CB(1)R) "Cis-On" agonist

Item Type:Article
Title:Development of an indole-amide-based photoswitchable cannabinoid receptor subtype 1 (CB(1)R) "Cis-On" agonist
Creators Name:Rodríguez-Soacha, D.A. and Steinmüller, S.A.M. and Işbilir, A. and Fender, J. and Deventer, M.H. and Ramírez, Y.A. and Tutov, A. and Sotriffer, C. and Stove, C.P. and Lorenz, K. and Lohse, M.J. and Hislop, J.N. and Decker, M.
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 CB(1)R (K(i) (cis-form) = 0.18 μM), with a marked difference in affinity with respect to its inactive "trans-off" form (CB(1)R 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 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 hCB(1)R in disorders associated with the endocannabinoid system.
Keywords:CB1 Agonist, G-Protein-Coupled Receptor, Diazocine, Optical Control, Photopharmacology, Photorimonabant
Source:ACS Chemical Neuroscience
ISSN:1948-7193
Publisher:American Chemical Society
Volume:13
Number:16
Page Range:2410–2435
Date:17 August 2022
Official Publication:https://doi.org/10.1021/acschemneuro.2c00160
PubMed:View item in PubMed

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