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

被引:72
作者
Selfridge, Brandon R. [1 ,2 ]
Wang, Xiaohui [3 ,4 ]
Zhang, Yingning [3 ]
Yin, Hang [4 ]
Grace, Peter M. [3 ]
Watkins, Linda R. [3 ]
Jacobson, Arthur E. [1 ,2 ]
Rice, Kenner C. [1 ,2 ]
机构
[1] Natl Inst Drug Abuse, Drug Design & Synth Sect, Mol Targets & Medicat Discovery Branch, Intramural Res Program, Bethesda, MD 20892 USA
[2] NIAAA, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA
[3] Univ Colorado, Dept Psychol & Neurosci, Boulder, CO 80309 USA
[4] Univ Colorado, Dept Chem & Biochem, BioFrontiers Inst, Boulder, CO 80309 USA
基金
澳大利亚国家健康与医学研究理事会;
关键词
NEUROPATHIC PAIN; NITRIC-OXIDE; NALTREXONE; NALOXONE; NEUROIMMUNOPHARMACOLOGY; NEUROINFLAMMATION; INFLAMMATION; RECOGNITION; ACTIVATION; MECHANISMS;
D O I
10.1021/acs.jmedchem.5b00426
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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.
引用
收藏
页码:5038 / 5052
页数:15
相关论文
共 40 条
  • [1] Bachtell R. K., 2015, CNS NEUROL DISORD DR
  • [2] Implications of central immune signaling caused by drugs of abuse: Mechanisms, mediators and new therapeutic approaches for prediction and treatment of drug dependence
    Coller, Janet K.
    Hutchinson, Mark R.
    [J]. PHARMACOLOGY & THERAPEUTICS, 2012, 134 (02) : 219 - 245
  • [3] PROBES FOR NARCOTIC RECEPTOR MEDIATED PHENOMENA .18. EPIMERIC 6-ALPHA-IODO-3,14-DIHYDROXY-17-(CYCLOPROPYLMETHYL)-4,5-ALPHA-EPOXYMORPHINANS AND 6-BETA-IODO-3,14-DIHYDROXY-17-(CYCLOPROPYLMETHYL)-4,5-ALPHA-EPOXYMORPHINANS AS POTENTIAL LIGANDS FOR OPIOID RECEPTOR SINGLE PHOTON-EMISSION COMPUTED-TOMOGRAPHY - SYNTHESIS, EVALUATION, AND RADIOCHEMISTRY OF [I-125] 6-BETA-IODO-3,14-DIHYDROXY-17-(CYCLOPROPYLMETHYL)-4,5-ALPHA-EPOXYMORPHINAN
    DECOSTA, BR
    IADAROLA, MJ
    ROTHMAN, RB
    BERMAN, KF
    GEORGE, C
    NEWMAN, AH
    MAHBOUBI, A
    JACOBSON, AE
    RICE, KC
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 1992, 35 (15) : 2826 - 2835
  • [4] Practical procedures for the preparation of N-tert-butyldimethylsilylhydrazones and their use in modified Wolff-Kishner reductions and in the synthesis of vinyl halides and gem-dihalides
    Furrow, ME
    Myers, AG
    [J]. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2004, 126 (17) : 5436 - 5445
  • [5] Pathological pain and the neuroimmune interface
    Grace, Peter M.
    Hutchinson, Mark R.
    Maier, Steven F.
    Watkins, Linda R.
    [J]. NATURE REVIEWS IMMUNOLOGY, 2014, 14 (04) : 217 - 231
  • [6] A NEW AND SENSITIVE METHOD FOR MEASURING THERMAL NOCICEPTION IN CUTANEOUS HYPERALGESIA
    HARGREAVES, K
    DUBNER, R
    BROWN, F
    FLORES, C
    JORIS, J
    [J]. PAIN, 1988, 32 (01) : 77 - 88
  • [7] Henn A, 2009, ALTEX-ALTERN TIEREXP, V26, P83
  • [8] Opioid Activation of Toll-Like Receptor 4 Contributes to Drug Reinforcement
    Hutchinson, M. R.
    Northcutt, A. L.
    Hiranita, T.
    Wang, X.
    Lewis, S. S.
    Thomas, J.
    van Steeg, K.
    Kopajtic, T. A.
    Loram, L. C.
    Sfregola, C.
    Galer, E.
    Miles, N. E.
    Bland, S. T.
    Amat, J.
    Rozeske, R. R.
    Maslanik, T.
    Chapman, T. R.
    Strand, K. A.
    Fleshner, M.
    Bachtell, R. K.
    Somogyi, A. A.
    Yin, H.
    Katz, J. L.
    Rice, K. C.
    Maier, S. F.
    Watkins, L. R.
    [J]. JOURNAL OF NEUROSCIENCE, 2012, 32 (33) : 11187 - 11200
  • [9] Hutchinson Mark R, 2007, ScientificWorldJournal, V7, P98
  • [10] Non-stereoselective reversal of neuropathic pain by naloxone and naltrexone: involvement of toll-like receptor 4 (TLR4)
    Hutchinson, Mark R.
    Zhang, Yingning
    Brown, Kimberley
    Coats, Benjamen D.
    Shridhar, Mitesh
    Sholar, Paige W.
    Patel, Sonica J.
    Crysdale, Nicole Y.
    Harrison, Jacqueline A.
    Maier, Steven F.
    Rice, Kenner C.
    Watkins, Linda R.
    [J]. EUROPEAN JOURNAL OF NEUROSCIENCE, 2008, 28 (01) : 20 - 29