2026-04-14T02:44:09Zhttps://recercat.cat/oai/request
oai:recercat.cat:2445/2185732025-11-19T20:41:46Zcom_2072_1057col_2072_478781col_2072_478917
RECERCAT author Navarro Brugal, Gemma author Gómez-Autet, Marc author Morales, Paula author Rebassa, Joan-Biel author Llinas Del Torrent, Claudia author Jagerovic, Nadine author Pardo, Leonardo author Franco Fernández, Rafael 2025-02-06T14:55:59Z2025-02-06T14:55:59Z2024-102025-02-06T14:55:59Z G protein-coupled receptors (GPCRs) exist within a landscape of interconvertible conformational states and in dynamic equilibrium between monomers and higher-order oligomers, both influenced by ligand binding. Here, we show that a homobivalent ligand formed by equal chromenopyrazole moieties as pharmacophores, connected by 14 methylene units, can modulate the dynamics of the cannabinoid CB2 receptor (CB2R) homodimerization by simultaneously binding both protomers of the CB2R-CB2R homodimer. Computational and pharmacological experiments showed that one of the ligand pharmacophores binds to the orthosteric site of one protomer, and the other pharmacophore to a membrane-oriented pocket between transmembranes 1 and 7 of the partner protomer. This results in unique pharmacological properties, including increased potency in Gi-mediated signaling and enhanced recruitment of β-arrestin. Thus, by modulating dimerization dynamics, it may be possible to fine-tune CB2R activity, potentially leading to improved therapeutic outcomes. cc-by-nc-nd (c) Navarro Brugal, Gemma et al., 2024 http://creativecommons.org/licenses/by-nc-nd/4.0/ info:eu-repo/semantics/openAccess Cànnabis Lligands (Bioquímica) Dinàmica molecular Cannabis Ligands (Biochemistry) Molecular dynamics Homodimerization of CB2 cannabinoid receptor triggered by a bivalent ligand enhances cellular signaling info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion