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Papers of the Week

Papers: 10 Sep 2022 - 16 Sep 2022

Pharmacology/Drug Development

2022 Aug 31

Eur J Med Chem


Benzo[b]thiophene-2-carboxamides as novel opioid receptor agonists with potent analgesic effect and reduced constipation.


Kuppusamy R, Hsu Y-T, Ke Y-Y, Chang P-W, Chang Y-C, Chang H-F, Wang P-C, Lin Y-H, Huang Y-C, Yeh T-K, Chuang J-Y, Loh HH, Shih C, Chen C-T, Yeh S-H, Ueng S-H
Eur J Med Chem. 2022 Aug 31; 243:114728.
PMID: 36084534.


Currently, there is a significant unmet need for novel analgesics with fewer side effects. In this study, we carried out structural modification of a hit compound previously identified in an artificial-intelligence (AI) virtual screening and discovered the potent analgesic, benzo[b]thiophene-2-carboxamide analog (compound 25) with new structural scaffold. We investigated the signaling pathways of opioid receptors mediated by compound 25, and found this racemic compound activated mu-opioid receptor through the cyclic adenosine monophosphate (cAMP) and β-arrestin-2-mediated pathways with strong potency and efficacy, and accompanying nociceptin-orphanin FQ opioid peptide and delta-opioid receptors through the cAMP pathway with weak potencies. Compound 25 elicited potent antinociception in thermal-stimulated pain (ED value of 127.1 ± 34.65 μg/kg) and inflammatory-induced allodynia models with less gastrointestinal transit inhibition and antinociceptive tolerance than morphine. Overall, this study revealed a novel analgesic with reduced risks of side effects.