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

doi:10.1016/j.ejmech.2022.114728

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 journal › Article › peer-review

3 Citations (Scopus)

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.

Original language	English
Article number	114728
Journal	European Journal of Medicinal Chemistry
Volume	243
DOIs	https://doi.org/10.1016/j.ejmech.2022.114728
Publication status	Published - Dec 2022

Keywords

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

ASJC Scopus subject areas

Pharmacology
Drug Discovery
Organic Chemistry

Access to Document

10.1016/j.ejmech.2022.114728

Cite this

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, H. H., Shih, C., Chen, C. T., Yeh, S. H., & Ueng, S. H. (2022). Benzo[b]thiophene-2-carboxamides as novel opioid receptor agonists with potent analgesic effect and reduced constipation. European Journal of Medicinal Chemistry, 243, Article 114728. https://doi.org/10.1016/j.ejmech.2022.114728

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 & Ueng, SH 2022, 'Benzo[b]thiophene-2-carboxamides as novel opioid receptor agonists with potent analgesic effect and reduced constipation', European Journal of Medicinal Chemistry, vol. 243, 114728. https://doi.org/10.1016/j.ejmech.2022.114728

@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 SAS",

}

TY - JOUR

T1 - Benzo[b]thiophene-2-carboxamides as novel opioid receptor agonists with potent analgesic effect and reduced constipation

AU - Kuppusamy, Ramajayam

AU - Hsu, Ying Ting

AU - Ke, Yi Yu

AU - Chang, Po Wei

AU - Chang, Yung Chiao

AU - Chang, Hsiao Fu

AU - Wang, Pei Chen

AU - Lin, Yu Hao

AU - Huang, Yu Chen

AU - Yeh, Teng Kuang

AU - Chuang, Jian Ying

AU - Loh, Horace H.

AU - Shih, Chuan

AU - Chen, Chiung Tong

AU - Yeh, Shiu Hwa

AU - Ueng, Shau Hua

N1 - 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: © 2022 Elsevier Masson SAS

PY - 2022/12

Y1 - 2022/12

N2 - 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.

AB - 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.

KW - Antinociception

KW - Antinociceptive tolerance

KW - Constipation

KW - Mu-opioid receptor

KW - Reward effect

KW - Structure-activity relationship study

UR - http://www.scopus.com/inward/record.url?scp=85137302073&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85137302073&partnerID=8YFLogxK

U2 - 10.1016/j.ejmech.2022.114728

DO - 10.1016/j.ejmech.2022.114728

M3 - Article

C2 - 36084534

AN - SCOPUS:85137302073

SN - 0223-5234

VL - 243

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

M1 - 114728

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this