2. Academic Validation
  3. DBPR116, a Prodrug of BPRMU191, in Combination with Naltrexone as a Safer Opioid Analgesic Than Morphine via Peripheral Administration

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

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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