Discovery of a Peripherally Directed CB1 Receptor Antagonist That Restores Insulin Signaling in Adipocytes
5 affiliations
- 1Universidade de Santiago de Compostela , , ,
- 2Università degli Studi di Bari ALDO MORO , , via Orabona 4 , ,
- 3CNR─Institute of Crystallography , Via Giovanni Amendola, 122/O , ,
- 4Instituto de Salud Carlos III , , ,
- 5Celtarys Research , Avenida de Barcelona, 7 , ,
Abstract
The antagonism of cannabinoid 1 receptor (CB1R) signaling has demonstrated clinical efficacy in treating obesity, improving insulin resistance, enhancing cardiovascular health, and mitigating metabolic risk factors in humans. Despite these positive outcomes, the clinical use of rimonabant was limited by severe central nervous system adverse effects, which reduced interest in CB1R and hindered the exploration of new therapeutic opportunities. Selective targeting of peripheral CB1R represents a promising strategy to overcome these limitations, creating therapeutic opportunities not only for obesity and metabolic disorders but also for smoking and alcohol addiction. Herein, we report a library of 53 novel, potent, and subtype-selective CB1R antagonists bearing polar groups, designed through convergent Ugi-based synthetic pathways. This approach enabled the identification of key structure–activity relationship features within this series and the effective modulation of molecular properties governing blood–brain barrier permeability. Among the compounds evaluated, the piperazine-1-ium derivative 24a stands out as the first permanently charged CB1R antagonist, exhibiting nanomolar affinity (Ki = 115 nM) and high CB1R/CB2R selectivity with a favorable physicochemical profile consistent with peripheral restriction and limited blood-brain barrier penetration. Importantly, 24a exhibits robust functional activity in a biologically relevant model of metabolic dysfunction. In insulin-resistant, lipid-hypertrophied adipocytes, 24a restores insulin-stimulated Akt phosphorylation and significantly enhances lipolytic activity, with effects comparable or superior to those of rimonabant at equivalent concentrations. These findings establish 24a as a promising peripherally restricted CB1R antagonist with demonstrated functional efficacy in a metabolic disease-relevant cellular model.
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BibTeX
@article{azuaje2026discovery,
title = {{Discovery of a Peripherally Directed CB1 Receptor Antagonist That Restores Insulin Signaling in Adipocytes}},
author = {Jhonny Azuaje and Rubén Prieto-Díaz and Claudia Gioé-Gallo and Sandra Ortigueira and Jacobo Soilán and Diego Triñanes and Hugo Fojo and María I. Loza and Marialessandra Contino and Maria Grazia Perrone and Giuseppe Felice Mangiatordi and Pietro Delre and Nerea Lago-Baameiro and Adriana Estévez-López and Maria Pardo and Angela Stefanachi and Giovanni Graziano and José Brea and Maria Majellaro and Eddy Sotelo},
journal = {ACS Omega},
year = {2026},
month = oct,
doi = {10.1021/acsomega.6c07565},
url = {https://pubs.acs.org/acsodf/article/11/42/65239/5450182/Discovery-of-a-Peripherally-Directed-CB1-Receptor},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Discovery of a Peripherally Directed CB1 Receptor Antagonist That Restores Insulin Signaling in Adipocytes
AU - Jhonny Azuaje
AU - Rubén Prieto-Díaz
AU - Claudia Gioé-Gallo
AU - Sandra Ortigueira
AU - Jacobo Soilán
AU - Diego Triñanes
AU - Hugo Fojo
AU - María I. Loza
AU - Marialessandra Contino
AU - Maria Grazia Perrone
AU - Giuseppe Felice Mangiatordi
AU - Pietro Delre
AU - Nerea Lago-Baameiro
AU - Adriana Estévez-López
AU - Maria Pardo
AU - Angela Stefanachi
AU - Giovanni Graziano
AU - José Brea
AU - Maria Majellaro
AU - Eddy Sotelo
PY - 2026
DA - 2026/10/13
JO - ACS Omega
DO - 10.1021/acsomega.6c07565
UR - https://pubs.acs.org/acsodf/article/11/42/65239/5450182/Discovery-of-a-Peripherally-Directed-CB1-Receptor
AB - The antagonism of cannabinoid 1 receptor (CB1R) signaling has demonstrated clinical efficacy in treating obesity, improving insulin resistance, enhancing cardiovascular health, and mitigating metabolic risk factors in humans. Despite these positive outcomes, the clinical use of rimonabant was limited by severe central nervous system adverse effects, which reduced interest in CB1R and hindered the exploration of new therapeutic opportunities. Selective targeting of peripheral CB1R represents a promising strategy to overcome these limitations, creating therapeutic opportunities not only for obesity and metabolic disorders but also for smoking and alcohol addiction. Herein, we report a library of 53 novel, potent, and subtype-selective CB1R antagonists bearing polar groups, designed through convergent Ugi-based synthetic pathways. This approach enabled the identification of key structure–activity relationship features within this series and the effective modulation of molecular properties governing blood–brain barrier permeability. Among the compounds evaluated, the piperazine-1-ium derivative 24a stands out as the first permanently charged CB1R antagonist, exhibiting nanomolar affinity (Ki = 115 nM) and high CB1R/CB2R selectivity with a favorable physicochemical profile consistent with peripheral restriction and limited blood-brain barrier penetration. Importantly, 24a exhibits robust functional activity in a biologically relevant model of metabolic dysfunction. In insulin-resistant, lipid-hypertrophied adipocytes, 24a restores insulin-stimulated Akt phosphorylation and significantly enhances lipolytic activity, with effects comparable or superior to those of rimonabant at equivalent concentrations. These findings establish 24a as a promising peripherally restricted CB1R antagonist with demonstrated functional efficacy in a metabolic disease-relevant cellular model.
SN - 2470-1343
ER -