DBPR116, a Prodrug of BPRMU191, in Combination with Naltrexone as a Safer Opioid Analgesic Than Morphine via Peripheral Administration

  • J Med Chem. 2024 Nov 14;67(21):19777-19790. doi: 10.1021/acs.jmedchem.4c02107.
Shu-Yu Lin  1 ,  Yung-Chiao Chang  1 ,  Ya-Wen Tien  1 ,  Yu-Hsien Kuo  1 ,  Hsiao-Fu Chang  1 ,  Li-Chin Ou  1 ,  Ya-Ping Chen  1 ,  Kuei-Hua Chang  1 ,  Ying-Ting Hsu  1 ,  Yu-Chen Huang  1 ,  Chen-Ming Yang  1 ,  Ping-Yee Law  2 ,  Jing-Hua Xi  3 ,  Pao-Luh Tao  4 ,  Horace H Loh  3  2 ,  Teng-Kuang Yeh  1 ,  Hong Zhuang  1 ,  Hsing-Pang Hsieh  1 ,  Chuan Shih  1 ,  Chiung-Tong Chen  1 ,  Shiu-Hwa Yeh  1  5 ,  Shau-Hua Ueng  1  6
Affiliations
  • 1. Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 35053, Taiwan R. O. C.
  • 2. Department of Pharmacology, University of Minnesota, Medical School, Minneapolis, Minnesota 55455, United States.
  • 3. Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou 510005, China.
  • 4. Center for Neuropsychiatric Research, National Health Research Institutes, Miaoli County 35053, Taiwan R. O. C.
  • 5. The PhD Program for Neural Regenerative Medicine, Taipei Medical University, Taipei 110, Taiwan R. O. C.
  • 6. School of Pharmacy, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan R. O. C.
PMID: 39473174 DOI: 10.1021/acs.jmedchem.4c02107
Abstract

The development of opioid analgesics with reduced adverse effects is an unmet need. In a previous study, we discovered a unique combination of BPRMU191 and morphinan antagonists that produced potent antinociception with reduced adverse effects after central administration (intrathecal or intracerebroventricular). BPRMU191/naltrexone exhibits notable in vitro and in vivo pharmacological properties. However, the poor blood-brain barrier penetrative ability of BPRMU191 restricts its clinical application. In this study, we utilized a prodrug strategy to deliver sufficient brain concentrations of BPRMU191 and selected compound 2 (DBPR116) with the best physicochemical and pharmacological properties among Other in vivo active prodrugs. The in vivo pharmacological studies of compound 2/naltrexone, including thermally stimulated pain, Cancer pain, constipation, sedation, psychological dependence, heart rate, and respiratory frequency measurements, demonstrated that it was a safer opioid analgesic than morphine in pain control.

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