Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 58, Issue 12, Pages 5038-5052Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.5b00426
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Funding
- NIH Intramural Research Programs of the National Institute on Drug Abuse (NIDA)
- National Institute of Alcohol Abuse and Alcoholism
- Bioscience Discovery Evaluation Program of the state of Colorado
- NIH [GM101279]
- NHMRC CJ Martin Fellowship [IDD 1054091]
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Activation of Toll-like receptors has been linked to neuropathic pain aria 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 compound's 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 mu M/1.4 mu M) 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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