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

Ramajayam Kuppusamy, Ying Ting Hsu, Yi Yu Ke, Po Wei Chang, Yung Chiao Chang, Hsiao Fu Chang, Pei Chen Wang, Yu Hao Lin, Yu Chen Huang, Teng Kuang Yeh, Jian Ying Chuang, Horace H. Loh, Chuan Shih, Chiung Tong Chen, Shiu Hwa Yeh, Shau Hua Ueng

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)


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 (ED50 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.

Original languageEnglish
Article number114728
JournalEuropean Journal of Medicinal Chemistry
Publication statusPublished - Dec 2022


  • Antinociception
  • Antinociceptive tolerance
  • Constipation
  • Mu-opioid receptor
  • Reward effect
  • Structure-activity relationship study

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry


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