Novel compounds that interact with both leukotriene B4 receptors and vanilloid TRPV1 receptors.
The aim of this study was to investigate the interaction of a series of novel compounds with leukotriene B(4) receptors (BLT) and vanilloid receptor (TRPV1). First, we characterized leukotriene B(4) (LTB(4)) ethanolamide. In guinea pig isolated lung parenchyma, LTB(4) ethanolamide antagonized the contractile action of LTB(4) with an apparent K(B) value of 7.28 nM. Using a Boyden chamber assay, we demonstrated that this compound stimulated human neutrophil migration in a similar manner to LTB(4) but with lower efficacy. In rat TRPV1 (rTRPV1)-expressing Chinese hamster ovary (CHO) cells and dorsal root ganglion (DRG) neurons, LTB(4) and LTB(4) ethanolamide acted as low-efficacy agonists, increasing intracellular calcium concentration ([Ca(2+)](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 LTB(4) to induce migration, with pIC(50) 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 [Ca(2+)](i) with a pIC(50) 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.
McHugh
Douglas
D
Institute of Medical Sciences, University of Aberdeen, Scotland.
McMaster
R Shannon
RS
Pertwee
Roger G
RG
Roy
Sucharita
S
Mahadevan
Anu
A
Razdan
Raj K
RK
Ross
Ruth A
RA
D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006801:Humans; D007975:Leukotriene B4 / Q000031:analogs & derivatives* / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018102:Receptors, Leukotriene B4 / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D050916:TRPV Cation Channels / Q000378:metabolism*; D014162:Transfection
D018102:Receptors, Leukotriene B4; D011994:Recombinant Proteins; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D007975:Leukotriene B4; D002118:Calcium