Repurposing-Based Strategies to Identify Effective Adenosine Receptor Antagonists
- 1University of Cambridge , , Tennis Court Road , ,
- 2University of Florence , , Via Ugo Schiff 6 , ,
- 3King’s College London , , Stamford Street , ,
Abstract
In this study, we employed an extensive drug repurposing strategy to identify new and improved adenosine receptor (AR) antagonists, with the aim of uncovering alternative therapeutic applications for existing polycyclic drug-like molecules. The compounds selected from our library were initially tested using the NanoBRET assay, and the top hits were then subjected to a predictive molecular modeling study, which enabled us to guide the design of new adenosine A1 and A3 receptor (A1R/A3R) antagonists. This approach led to the identification of two lead candidates, which exhibit a different profile of affinity and selectivity toward the A1R and A3R subtypes, attributable to their specific structural features. In particular, compound 2v (based on a pyrazolo[1,5-a]pyrimidine scaffold) showed the highest affinity, with a 10-fold greater selectivity toward A1R (pKi of 8.18 ± 0.21 and 6.76 ± 0.11 on A1R and A3R, respectively). These results highlight the critical role of the substituted phenyl group at position 2 in conferring A1R selectivity. In contrast, compound 3f (based on a tricyclic scaffold) proved to be a potent and selective A3R antagonist (pKi = 6.94 for A1R and 8.22 for A3R). Collectively, these findings provide valuable insights for the development of improved small-molecule heterocyclic A1R/A3R antagonists and may support future therapeutic applications targeting these receptor subtypes.
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BibTeX
@article{pearce2026repurposingbased,
title = {{Repurposing-Based Strategies to Identify Effective Adenosine Receptor Antagonists}},
author = {Abigail Pearce and Letizia Crocetti and Qi Xu and Francesca Catarzi and Gabriella Guerrini and Zihan Shi and Ana Rossi and Alex Harper and Ayoola Ishola and Shahd Abdelrahman and Yashkumar Patel and Xianglin Huang and Silvia Selleri and Maria Paola Giovannoni and Agostino Cilibrizzi and Graham Ladds},
journal = {ACS Omega},
year = {2026},
month = oct,
doi = {10.1021/acsomega.6c07719},
url = {https://pubs.acs.org/acsodf/article/11/42/65290/5448928/Repurposing-Based-Strategies-to-Identify-Effective},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Repurposing-Based Strategies to Identify Effective Adenosine Receptor Antagonists
AU - Abigail Pearce
AU - Letizia Crocetti
AU - Qi Xu
AU - Francesca Catarzi
AU - Gabriella Guerrini
AU - Zihan Shi
AU - Ana Rossi
AU - Alex Harper
AU - Ayoola Ishola
AU - Shahd Abdelrahman
AU - Yashkumar Patel
AU - Xianglin Huang
AU - Silvia Selleri
AU - Maria Paola Giovannoni
AU - Agostino Cilibrizzi
AU - Graham Ladds
PY - 2026
DA - 2026/10/12
JO - ACS Omega
DO - 10.1021/acsomega.6c07719
UR - https://pubs.acs.org/acsodf/article/11/42/65290/5448928/Repurposing-Based-Strategies-to-Identify-Effective
AB - In this study, we employed an extensive drug repurposing strategy to identify new and improved adenosine receptor (AR) antagonists, with the aim of uncovering alternative therapeutic applications for existing polycyclic drug-like molecules. The compounds selected from our library were initially tested using the NanoBRET assay, and the top hits were then subjected to a predictive molecular modeling study, which enabled us to guide the design of new adenosine A1 and A3 receptor (A1R/A3R) antagonists. This approach led to the identification of two lead candidates, which exhibit a different profile of affinity and selectivity toward the A1R and A3R subtypes, attributable to their specific structural features. In particular, compound 2v (based on a pyrazolo[1,5-a]pyrimidine scaffold) showed the highest affinity, with a 10-fold greater selectivity toward A1R (pKi of 8.18 ± 0.21 and 6.76 ± 0.11 on A1R and A3R, respectively). These results highlight the critical role of the substituted phenyl group at position 2 in conferring A1R selectivity. In contrast, compound 3f (based on a tricyclic scaffold) proved to be a potent and selective A3R antagonist (pKi = 6.94 for A1R and 8.22 for A3R). Collectively, these findings provide valuable insights for the development of improved small-molecule heterocyclic A1R/A3R antagonists and may support future therapeutic applications targeting these receptor subtypes.
SN - 2470-1343
ER -