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, Brandon R Selfridge, Xiaohui Wang, Yingning Zhang, Hang Yin, Peter M Grace, Linda R Watkins, Arthur E Jacobson, Kenner C Rice
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.
Conflict of interest statement
The authors declare no competing financial interests.
Figures
![Figure 1](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4634939/bin/nihms733807f1.jpg)
![Figure 2](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4634939/bin/nihms733807f2.jpg)
![Figure 3](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4634939/bin/nihms733807f3.jpg)
![Figure 4](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4634939/bin/nihms733807f4.jpg)
![Figure 5](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4634939/bin/nihms733807f5.jpg)
![Figure 6](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4634939/bin/nihms733807f6.jpg)
![Figure 7](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4634939/bin/nihms733807f7.jpg)
![Figure 8](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4634939/bin/nihms733807f8.jpg)
![Scheme 1](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4634939/bin/nihms733807f9.jpg)
![Scheme 2](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4634939/bin/nihms733807f10.jpg)
![Scheme 3](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4634939/bin/nihms733807f11.jpg)
![Scheme 4](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4634939/bin/nihms733807f12.jpg)
![Scheme 5](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4634939/bin/nihms733807f13.jpg)
![Scheme 6](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4634939/bin/nihms733807f14.jpg)
![Scheme 7](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4634939/bin/nihms733807f15.jpg)
Source: PubMed