Structural Modification and Development of N-(1,2,3,4-Tetrahydro-3-isoquinolinylmethyl)benzamide, BPR1M492, as a Potent and Rapid-Onset Opioid Analgesic with Reduced Withdrawal Symptoms

  • J Med Chem. 2026 Jun 11;69(11):13222-13247. doi: 10.1021/acs.jmedchem.6c00215.
Po-Wei Chang  1 ,  Yung-Chiao Chang  1 ,  Ya-Wen Tien  1 ,  Hsiao-Fu Chang  1 ,  Sheng-Ren Chen  1 ,  Ya-Ping Chen  1 ,  Wei-Cheng Huang  1 ,  Chih-Chien Hsieh  1 ,  Ling Chang  1 ,  Hong Zhuang  1 ,  Teng-Kuang Yeh  1 ,  Chun-Wei Tung  1 ,  Shiu-Hwa Yeh  1  2 ,  Shau-Hua Ueng  1  3
Affiliations
  • 1. Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 35053, Taiwan, R.O.C.
  • 2. The Ph.D. Program in Medical Neuroscience, College of Medical Science and Technology, Taipei Medical University and National Health Research Institutes, Taipei 110, Taiwan, ROC.
  • 3. School of Pharmacy, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan, R.O.C.
PMID: 42224613 DOI: 10.1021/acs.jmedchem.6c00215
Abstract

A series of N-(1,2,3,4-tetrahydro-3-isoquinolinylmethyl)benzamides, which are potent μ-opioid receptor (MOR) agonists, has been discovered. The most promising compound, compound 56 (BPR1M492), is an MOR agonist without a clear signaling bias between cAMP and β-arrestin-2 pathways, a cAMP-biased nociceptin-orphanin FQ opioid peptide agonist, and a weak cAMP-biased δ/κ-opioid receptor agonist. Compound 56 demonstrated potent in vivo antinociception at 0.027 mg/kg, offering rapid pain relief within 5 min of subcutaneous injection. It produced markedly milder withdrawal symptoms than TRV130 in mice, whereas differences in respiratory, gastrointestinal, reward-related, and tolerance-related measures were less pronounced and should be interpreted cautiously in light of the substantially lower dose required for antinociception. Compound 56 is a highly stable, slightly hygroscopic, low-moisture-containing crystalline solid that is safe at its in vivo effective dose.

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