Selective and antagonist-dependent µ-opioid receptor activation by the combination of 2-{[2-(6-chloro-3,4-dihydro-1(2H)-quinolinyl)-2-oxoethyl]sulfanyl}-5-phenyl-4,6-(1H,5H)-pyrimidinedione and naloxone/naltrexone

Shu-Yu Lin; Ya-Wen Tien; Yi-Yu Ke; Yung-Chiao 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

doi:10.1016/j.bioorg.2022.105905

Selective and antagonist-dependent µ-opioid receptor activation by the combination of 2-{[2-(6-chloro-3,4-dihydro-1(2H)-quinolinyl)-2-oxoethyl]sulfanyl}-5-phenyl-4,6-(1H,5H)-pyrimidinedione and naloxone/naltrexone

Bioorg Chem. 2022 Nov:128:105905. doi: 10.1016/j.bioorg.2022.105905. Epub 2022 Jun 2.

Authors

Affiliations

¹ Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 35053, Taiwan, ROC.
² Department of Pharmacology, University of Minnesota, Medical School, Minneapolis, MN 55455, USA.
³ Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou 510005, China.
⁴ Center for Neuropsychiatric Research, National Health Research Institutes, Zhunan, Miaoli County, Taiwan, ROC.
⁵ Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou 510005, China; Department of Pharmacology, University of Minnesota, Medical School, Minneapolis, MN 55455, USA.
⁶ Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 35053, Taiwan, ROC; The PhD Program for Neural Regenerative Medicine, Taipei Medical University, Taipei 110, Taiwan, ROC. Electronic address: bau9763@nhri.edu.tw.
⁷ Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 35053, Taiwan, ROC; School of Pharmacy, National Cheng Kung University, Tainan, Taiwan, ROC. Electronic address: shueng@nhri.org.tw.

PMID: 35710525
DOI: 10.1016/j.bioorg.2022.105905

Abstract

We identified, via high-throughput screening using a FLIPR® calcium assay, compound 1, which incorporated a dihydroquinolinyl-2-oxoethylsulfanyl-(1H,5H)-pyrimidinedione core and activated the μ-opioid receptor (MOR) in the presence of naloxone or naltrexone. A structure-activity relationship study of the analogs of 1 led to the design of compound 21, which activated MOR in the presence of naloxone with an EC₅₀ of 3.3 ± 0.2 μM. MOR activation by the compound 21-antagonist pair was antagonist-dependent. Compound 21 did not affect the potency of the orthosteric agonist, morphine, toward MOR, indicating that it affected the function of MOR antagonists rather than that of the agonists. Computer modeling of the compound 21-MOR-naloxone complex revealed major interactions between compound 21 and MOR, including hydrogen bonding with Ser196, π-π stacking with Tyr149, and sulfur-aromatic interaction with Trp192. This study may pave the way for developing agents capable of safe and effective MOR modulation.

Keywords: Alkaloid antagonist; Antagonist dependent; High-throughput screen; Naloxone; Naltrexone; Opioid receptor activation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Analgesics, Opioid
Imidazoles
Naloxone* / pharmacology
Naltrexone* / pharmacology
Receptors, Opioid
Sulfonamides
Thiophenes

Substances

Analgesics, Opioid
Imidazoles
Receptors, Opioid
Sulfonamides
Thiophenes
Naloxone
Naltrexone
compound 21