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NEUROPHARMACOLOGY

Novel Compounds That Interact with Both Leukotriene B₄ Receptors and Vanilloid TRPV1 Receptors

Institute of Medical Sciences, University of Aberdeen, Aberdeen, Scotland (D.M., R.S.M., R.G.P, R.A.R.); and Organix Inc., Woburn, Massachusetts (S.R., A.M., R.K.R.)

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 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 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.

Address correspondence to: Dr. R. A. Ross, Department of Biomedical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, Scotland, UK. E-mail: r.ross{at}abdn.ac.uk

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