The in vivo antinociceptive and μ-opioid receptor activating effects of the combination of N-phenyl-2′,4′-dimethyl-4,5′-bi-1,3-thiazol-2-amines and naloxone

Shu Yu Lin, Yu Hsien Kuo, Ya Wen Tien, Yi Yu Ke, Wan Ting Chang, Hsiao Fu Chang, Li Chin Ou, Ping-Yee Law, Jing Hua Xi, Pao Luh Tao, Horace H Loh, Yu Sheng Chao, Chuan Shih, Chiung Tong Chen, Shiu Hwa Yeh, Shau Hua Ueng

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Morphine is widely used for the treatment of severe pain. This analgesic effect is mediated principally by the activation of μ-opioid receptors (MOR). However, prolonged activation of MOR also results in tolerance, dependence, addiction, constipation, nausea, sedation, and respiratory depression. To address this problem, we sought alternative ways to activate MOR – either by use of novel ligands, or via a novel activation mechanism. To this end, a series of compounds were screened using a sensitive CHO-K1/MOR/Gα15 cell-based FLIPR® calcium high-throughput screening (HTS) assay, and the bithiazole compound 5a was identified as being able activate MOR in combination with naloxone. Structural modifications of 5a resulted in the discovery of lead compound 5j, which could effectively activate MOR in combination with the MOR antagonist naloxone or naltrexone. In vivo, naloxone in combination with 100 mg/kg of compound 5j elicited antinociception in a mouse tail-flick model with an ED50 of 17.5 ± 4 mg/kg. These results strongly suggest that the mechanism by which the 5j/naloxone combination activates MOR is worthy of further study, as its discovery has the potential to yield an entirely novel class of analgesics.

Original languageEnglish (US)
Pages (from-to)312-323
Number of pages12
JournalEuropean Journal of Medicinal Chemistry
Volume167
DOIs
StatePublished - Apr 1 2019

Fingerprint

Opioid Receptors
Naloxone
Amines
Chemical activation
Analgesics
High-Throughput Screening Assays
Lead compounds
Naltrexone
Constipation
Respiratory Insufficiency
Morphine
Nausea
Tail
Assays
Screening
Throughput
Ligands
Calcium
Pain
Therapeutics

Keywords

  • Antagonist
  • Antinociception
  • High-throughput screen
  • Naloxone
  • Naltrexone
  • Opioid receptor activation

PubMed: MeSH publication types

  • Journal Article

Cite this

The in vivo antinociceptive and μ-opioid receptor activating effects of the combination of N-phenyl-2′,4′-dimethyl-4,5′-bi-1,3-thiazol-2-amines and naloxone. / Lin, Shu Yu; Kuo, Yu Hsien; Tien, Ya Wen; Ke, Yi Yu; Chang, Wan Ting; Chang, Hsiao Fu; Ou, Li Chin; Law, Ping-Yee; Xi, Jing Hua; Tao, Pao Luh; Loh, Horace H; Chao, Yu Sheng; Shih, Chuan; Chen, Chiung Tong; Yeh, Shiu Hwa; Ueng, Shau Hua.

In: European Journal of Medicinal Chemistry, Vol. 167, 01.04.2019, p. 312-323.

Research output: Contribution to journalArticle

Lin, Shu Yu ; Kuo, Yu Hsien ; Tien, Ya Wen ; Ke, Yi Yu ; Chang, Wan Ting ; Chang, Hsiao Fu ; Ou, Li Chin ; Law, Ping-Yee ; Xi, Jing Hua ; Tao, Pao Luh ; Loh, Horace H ; Chao, Yu Sheng ; Shih, Chuan ; Chen, Chiung Tong ; Yeh, Shiu Hwa ; Ueng, Shau Hua. / The in vivo antinociceptive and μ-opioid receptor activating effects of the combination of N-phenyl-2′,4′-dimethyl-4,5′-bi-1,3-thiazol-2-amines and naloxone. In: European Journal of Medicinal Chemistry. 2019 ; Vol. 167. pp. 312-323.
@article{d2f85361425c4a219b7309bb9f75a146,
title = "The in vivo antinociceptive and μ-opioid receptor activating effects of the combination of N-phenyl-2′,4′-dimethyl-4,5′-bi-1,3-thiazol-2-amines and naloxone",
abstract = "Morphine is widely used for the treatment of severe pain. This analgesic effect is mediated principally by the activation of μ-opioid receptors (MOR). However, prolonged activation of MOR also results in tolerance, dependence, addiction, constipation, nausea, sedation, and respiratory depression. To address this problem, we sought alternative ways to activate MOR – either by use of novel ligands, or via a novel activation mechanism. To this end, a series of compounds were screened using a sensitive CHO-K1/MOR/Gα15 cell-based FLIPR{\circledR} calcium high-throughput screening (HTS) assay, and the bithiazole compound 5a was identified as being able activate MOR in combination with naloxone. Structural modifications of 5a resulted in the discovery of lead compound 5j, which could effectively activate MOR in combination with the MOR antagonist naloxone or naltrexone. In vivo, naloxone in combination with 100 mg/kg of compound 5j elicited antinociception in a mouse tail-flick model with an ED50 of 17.5 ± 4 mg/kg. These results strongly suggest that the mechanism by which the 5j/naloxone combination activates MOR is worthy of further study, as its discovery has the potential to yield an entirely novel class of analgesics.",
keywords = "Antagonist, Antinociception, High-throughput screen, Naloxone, Naltrexone, Opioid receptor activation",
author = "Lin, {Shu Yu} and Kuo, {Yu Hsien} and Tien, {Ya Wen} and Ke, {Yi Yu} and Chang, {Wan Ting} and Chang, {Hsiao Fu} and Ou, {Li Chin} and Ping-Yee Law and Xi, {Jing Hua} and Tao, {Pao Luh} and Loh, {Horace H} and Chao, {Yu Sheng} and Chuan Shih and Chen, {Chiung Tong} and Yeh, {Shiu Hwa} and Ueng, {Shau Hua}",
year = "2019",
month = "4",
day = "1",
doi = "10.1016/j.ejmech.2019.01.063",
language = "English (US)",
volume = "167",
pages = "312--323",
journal = "European Journal of Medicinal Chemistry",
issn = "0223-5234",
publisher = "Elsevier Masson SAS",

}

TY - JOUR

T1 - The in vivo antinociceptive and μ-opioid receptor activating effects of the combination of N-phenyl-2′,4′-dimethyl-4,5′-bi-1,3-thiazol-2-amines and naloxone

AU - Lin, Shu Yu

AU - Kuo, Yu Hsien

AU - Tien, Ya Wen

AU - Ke, Yi Yu

AU - Chang, Wan Ting

AU - Chang, Hsiao Fu

AU - Ou, Li Chin

AU - Law, Ping-Yee

AU - Xi, Jing Hua

AU - Tao, Pao Luh

AU - Loh, Horace H

AU - Chao, Yu Sheng

AU - Shih, Chuan

AU - Chen, Chiung Tong

AU - Yeh, Shiu Hwa

AU - Ueng, Shau Hua

PY - 2019/4/1

Y1 - 2019/4/1

N2 - Morphine is widely used for the treatment of severe pain. This analgesic effect is mediated principally by the activation of μ-opioid receptors (MOR). However, prolonged activation of MOR also results in tolerance, dependence, addiction, constipation, nausea, sedation, and respiratory depression. To address this problem, we sought alternative ways to activate MOR – either by use of novel ligands, or via a novel activation mechanism. To this end, a series of compounds were screened using a sensitive CHO-K1/MOR/Gα15 cell-based FLIPR® calcium high-throughput screening (HTS) assay, and the bithiazole compound 5a was identified as being able activate MOR in combination with naloxone. Structural modifications of 5a resulted in the discovery of lead compound 5j, which could effectively activate MOR in combination with the MOR antagonist naloxone or naltrexone. In vivo, naloxone in combination with 100 mg/kg of compound 5j elicited antinociception in a mouse tail-flick model with an ED50 of 17.5 ± 4 mg/kg. These results strongly suggest that the mechanism by which the 5j/naloxone combination activates MOR is worthy of further study, as its discovery has the potential to yield an entirely novel class of analgesics.

AB - Morphine is widely used for the treatment of severe pain. This analgesic effect is mediated principally by the activation of μ-opioid receptors (MOR). However, prolonged activation of MOR also results in tolerance, dependence, addiction, constipation, nausea, sedation, and respiratory depression. To address this problem, we sought alternative ways to activate MOR – either by use of novel ligands, or via a novel activation mechanism. To this end, a series of compounds were screened using a sensitive CHO-K1/MOR/Gα15 cell-based FLIPR® calcium high-throughput screening (HTS) assay, and the bithiazole compound 5a was identified as being able activate MOR in combination with naloxone. Structural modifications of 5a resulted in the discovery of lead compound 5j, which could effectively activate MOR in combination with the MOR antagonist naloxone or naltrexone. In vivo, naloxone in combination with 100 mg/kg of compound 5j elicited antinociception in a mouse tail-flick model with an ED50 of 17.5 ± 4 mg/kg. These results strongly suggest that the mechanism by which the 5j/naloxone combination activates MOR is worthy of further study, as its discovery has the potential to yield an entirely novel class of analgesics.

KW - Antagonist

KW - Antinociception

KW - High-throughput screen

KW - Naloxone

KW - Naltrexone

KW - Opioid receptor activation

UR - http://www.scopus.com/inward/record.url?scp=85061576132&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85061576132&partnerID=8YFLogxK

U2 - 10.1016/j.ejmech.2019.01.063

DO - 10.1016/j.ejmech.2019.01.063

M3 - Article

C2 - 30776693

AN - SCOPUS:85061576132

VL - 167

SP - 312

EP - 323

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

SN - 0223-5234

ER -