Abstract
The aim of this study was to investigate the interaction of a series of novel compounds with leukotriene B4 receptors (BLT) and vanilloid receptor (TRPV1). First, we characterized leukotriene B4 (LTB4) ethanolamide. In guinea pig isolated lung parenchyma, LTB4 ethanolamide antagonized the contractile action of LTB4 with an apparent KB value of 7.28 nM. Using a Boyden chamber assay, we demonstrated that this compound stimulated human neutrophil migration in a similar manner to LTB4 but with lower efficacy. In rat TRPV1 (rTRPV1)-expressing Chinese hamster ovary (CHO) cells and dorsal root ganglion (DRG) neurons, LTB4 and LTB4 ethanolamide acted as low-efficacy agonists, increasing intracellular calcium concentration ([Ca2+]i) in a capsazepine-sensitive manner. These results prompted us to hypothesize that a molecule may possess pharmacophores such that it is capable of dual antagonism of BLT and TRPV1 receptors. Two novel compounds, N-{2-fluoro-4-[3-(11 hydroxyheptadec-8-enyl)-thioureiomethyl]-phenyl}-methanesulfonamide (O-3367) and N-{4-[3-(11 hydroxyheptadec-8-enyl)-thioureio-methyl]-phenyl}-methanesulfonamide (O-3383), were synthesized. In human neutrophils, both compounds acted as antagonists, significantly attenuating the BLT receptor-mediated ability of LTB4 to induce migration, with pIC50 values of 7.22 ± 0.17 and 5.95 ± 0.16, respectively. In rTRPV1-expressing CHO cells, they caused a significant rightward shift in the log concentration-response curve for the TRPV1 receptor agonist capsaicin (3-methoxy-4-hydroxy)benzyl-8-methyl-6-nonenamide). In DRG neurons O-3367 significantly attenuated the capsaicin-induced increases in [Ca2+]i with a pIC50 value of 5.94 ± 0.004. O-3367 and O-3383 represent novel structural templates for generating compounds possessing dual antagonism at BLT and TRPV1 receptors. In view of the crucial role of both TRPV1 and BLT receptors in the pathophysiology of inflammatory conditions, such compounds may betoken a novel class of highly effective therapeutics.
Footnotes
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This work was supported by grants from Allergan Inc. (Irvine, CA) (to R.A.R. and D.M.) and National Institutes of Health (to R.R., R.G.P., and R.A.R.).
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doi:10.1124/jpet.105.095992.
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ABBREVIATIONS: LTB4, leukotriene B4, 5(S),12(R)dihydroxy-6,14-cis-8,10 trans-eicosatetraenoic acid); BLT, leukotriene B4 receptor; TRPV1, vanilloid receptor; O-3367, N-{2-fluoro-4-[3-(11-hydroxyheptadec-8-enyl)-thioureio-methyl]-phenyl}-methanesulfonamide; O-3383, N-{4-[3-(11 hydroxyheptadec-8-enyl)-thioureio-methyl]-phenyl}-methanesulfonamide; CHO, Chinese hamster ovary; LTB4 ethanolamide, 5(S),12(R)dihydroxy-6,14-cis-8,10 trans-eicosatetraenoic ethanolamide; U75302, LTB4 dimethylamide, 5(S),12(R)dihydroxy-6,14-cis-8,10 trans-eicosatetraenoic dimethylamide; DRG, dorsal root ganglion; fMLP, N-formyl-methionyl-leucyl-phenylalanine; rTRPV1, rat vanilloid receptor; DMSO, dimethyl sulfoxide; ANOVA, analysis of variance; [Ca2+]i, intracellular calcium concentration; FAAH, fatty acid amide hydrolase; LY293111, sodium (2-[2-propyl-3-[2-ethyl-4-(4-fluorophenyl0-5-hydroxyphenoxy]propoxy]phenoxy]benzoic acid sodium salt; U75302, 6-(6-(3-hydroxy-1E,5Z-undecadienyl)-2-pyridnyl)-1,5-hexane diol.
- Received September 21, 2005.
- Accepted September 30, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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