1. Benzo[b]thiophene-2-carboxamides as novel opioid receptor agonists with potent analgesic effect and reduced constipation.
- Author
-
Kuppusamy R, Hsu YT, Ke YY, Chang PW, Chang YC, Chang HF, Wang PC, Lin YH, Huang YC, Yeh TK, Chuang JY, Loh HH, Shih C, Chen CT, Yeh SH, and Ueng SH
- Subjects
- Humans, Receptors, Opioid, mu agonists, Receptors, Opioid agonists, Opioid Peptides, Morphine pharmacology, Analgesics pharmacology, Analgesics therapeutic use, Analgesics chemistry, Constipation chemically induced, Constipation drug therapy, Thiophenes pharmacology, Thiophenes therapeutic use, Analgesics, Opioid adverse effects
- Abstract
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
50 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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)- Published
- 2022
- Full Text
- View/download PDF