Structure-Activity Relationships of (+)-Naltrexone-Inspired Toll-like Receptor 4 (TLR4) Antagonists

Brandon R. Selfridge, Xiaohui Wang, Yingning Zhang, Hang Yin, Peter M. Grace, Linda R. Watkins, Arthur E. Jacobson, Kenner C. Rice

Research output: Contribution to journalArticle

32 Scopus citations


Activation of Toll-like receptors has been linked to neuropathic pain and opioid dependence. (+)-Naltrexone acts as a Toll-like receptor 4 (TLR4) antagonist and has been shown to reverse neuropathic pain in rat studies. We designed and synthesized compounds based on (+)-naltrexone and (+)-noroxymorphone and evaluated their TLR4 antagonist activities by their effects on inhibiting lipopolysaccharide (LPS) induced TLR4 downstream nitric oxide (NO) production in microglia BV-2 cells. Alteration of the N-substituent in (+)-noroxymorphone gave us a potent TLR4 antagonist. The most promising analog, (+)-N-phenethylnoroxymorphone ((4S,4aR,7aS,12bR)-4a,9-dihydroxy-3-phenethyl-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one, 1j) showed ∼75 times better TLR-4 antagonist activity than (+)-naltrexone, and the ratio of its cell viability IC50, a measure of its toxicity, to TLR-4 antagonist activity (140 μM/1.4 μM) was among the best of the new analogs. This compound (1j) was active in vivo; it significantly increased and prolonged morphine analgesia.

Original languageEnglish (US)
Pages (from-to)5038-5052
Number of pages15
JournalJournal of Medicinal Chemistry
Issue number12
StatePublished - Jun 25 2015

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Selfridge, B. R., Wang, X., Zhang, Y., Yin, H., Grace, P. M., Watkins, L. R., Jacobson, A. E., & Rice, K. C. (2015). Structure-Activity Relationships of (+)-Naltrexone-Inspired Toll-like Receptor 4 (TLR4) Antagonists. Journal of Medicinal Chemistry, 58(12), 5038-5052.