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https://hdl.handle.net/2440/133553
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Type: | Journal article |
Title: | Structure-Activity Relationships of (+)-Naltrexone-Inspired Toll-like Receptor 4 (TLR4) Antagonists |
Author: | Selfridge, B.R. Wang, X. Zhang, Y. Yin, H. Grace, P.M. Watkins, L.R. Jacobson, A.E. Rice, K.C. |
Citation: | Journal of Medicinal Chemistry, 2015; 58(12):5038-5052 |
Publisher: | ACS Publications |
Issue Date: | 2015 |
ISSN: | 0022-2623 1520-4804 |
Statement of Responsibility: | Brandon R. Selfridge, Xiaohui Wang, Yingning Zhang, Hang Yin, Peter M. Grace, Linda R. Watkins, Arthur E. Jacobson, and 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 TLR4 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. |
Keywords: | Salts; Purification; Solutions; Antagonists; Mixtures |
Rights: | © 2015 American Chemical Society |
DOI: | 10.1021/acs.jmedchem.5b00426 |
Grant ID: | http://purl.org/au-research/grants/nhmrc/1054091 |
Published version: | http://dx.doi.org/10.1021/acs.jmedchem.5b00426 |
Appears in Collections: | Medicine publications |
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