2. Academic Validation
  3. Structure-Activity Relationships of (+)-Naltrexone-Inspired Toll-like Receptor 4 (TLR4) Antagonists

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

  • J Med Chem. 2015 Jun 25;58(12):5038-52. doi: 10.1021/acs.jmedchem.5b00426.
Brandon R Selfridge 1,  Xiaohui Wang 2 3,  Yingning Zhang 2,  Hang Yin 3,  Peter M Grace 2,  Linda R Watkins 2,  Arthur E Jacobson 1,  Kenner C Rice 1
Affiliations

Affiliations

  • 1 †Drug Design and Synthesis Section, Molecular Targets and Medications Discovery Branch, Intramural Research Program, National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Department of Health and Human Services, 9800 Medical Center Drive, Bethesda, Maryland 20892-3373, United States.
  • 2 ‡Department of Psychology and Neuroscience, University of Colorado at Boulder, Boulder, Colorado 80309, United States.
  • 3 §Department of Chemistry and Biochemistry the BioFrontiers Institute, University of Colorado at Boulder, Boulder, Colorado 80309, United States.
PMID: 26010811 DOI: 10.1021/acs.jmedchem.5b00426
Abstract

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.

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