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

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• 作者：Brandon R. Selfridge ; Xiaohui Wang ; Yingning Zhang ; Hang Yin ; Peter M. Grace ; Linda R. Watkins ; Arthur E. Jacobson ; Kenner C. Rice
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：June 25, 2015
• 年：2015
• 卷：58
• 期：12
• 页码：5038-5052
• 全文大小：703K
• ISSN：1520-4804

文摘

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 鈭?5 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 渭M/1.4 渭M) was among the best of the new analogs. This compound (1j) was active in vivo; it significantly increased and prolonged morphine analgesia.