@article{fadf534c6c2c46b5bc38e5d9950b7966,
title = "Benzo[b]thiophene-2-carboxamides as novel opioid receptor agonists with potent analgesic effect and reduced constipation",
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 (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.",
keywords = "Antinociception, Antinociceptive tolerance, Constipation, Mu-opioid receptor, Reward effect, Structure-activity relationship study",
author = "Ramajayam Kuppusamy and Hsu, {Ying Ting} and Ke, {Yi Yu} and Chang, {Po Wei} and Chang, {Yung Chiao} and Chang, {Hsiao Fu} and Wang, {Pei Chen} and Lin, {Yu Hao} and Huang, {Yu Chen} and Yeh, {Teng Kuang} and Chuang, {Jian Ying} and Loh, {Horace H.} and Chuan Shih and Chen, {Chiung Tong} and Yeh, {Shiu Hwa} and Ueng, {Shau Hua}",
note = "Funding Information: We are grateful to the grants 107-2635-B-400-001 , 108-2320-B-400-014-MY3 , 109-2320-B-400-015 , and 110-2320-B-400-004-MY2 obtained from the Ministry of Science and Technology , Taiwan, and Intramural Research Program of National Health Research Institutes . We also thank Dr. Hsin-Ru Wu of the Instrumentation Center of National Tsing Hua University for HPLC MS measurements. Funding Information: We are grateful to the grants 107-2635-B-400-001, 108-2320-B-400-014-MY3, 109-2320-B-400-015, and 110-2320-B-400-004-MY2 obtained from the Ministry of Science and Technology, Taiwan, and Intramural Research Program of National Health Research Institutes. We also thank Dr. Hsin-Ru Wu of the Instrumentation Center of National Tsing Hua University for HPLC MS measurements. Publisher Copyright: {\textcopyright} 2022 Elsevier Masson SAS",
year = "2022",
month = dec,
doi = "10.1016/j.ejmech.2022.114728",
language = "English",
volume = "243",
journal = "European Journal of Medicinal Chemistry",
issn = "0223-5234",
publisher = "Elsevier Masson s.r.l.",
}