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Design of a High-Affinity Competitive Antagonist of the Vanilloid Receptor Selective for the Calcium Entry-Linked Receptor Population

Molecular Mechanisms of Tumor Promotion Section, Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (A.T., P.M.B.); and Department of Medicinal Chemistry and Pharmacology, University of Illinois at Chicago, Chicago, Illinois) (Z.C., A.P.K.)

We describe the synthesis and characterization of N-(4-chlorobenzyl) -N'-(4-hydroxy-3-iodo-5-methoxybenzyl)thiourea (IBTU), a novel antagonist of the vanilloid receptor 1 (TRPV1 or VR1). IBTU competitively inhibited ⁴⁵Ca²⁺ uptake into CHO cells heterologously expressing rat TRPV1, whether induced by capsaicin or resiniferatoxin (K_i = 99 ± 23 and 93 ± 34 nM, respectively). IBTU was thus somewhat more potent (5-fold) than capsazepine. In contrast to its antagonism of vanilloid-induced calcium uptake, IBTU (30 µM) inhibited [³H]resiniferatoxin binding to TRPV1 by less than 10%. We hypothesize that these dramatically distinct potencies reflect different fractions of TRPV1 in this system: namely, a minor plasma membrane fraction controlling ⁴⁵Ca²⁺ uptake, and the predominant intracellular fraction that dominates the [³H]resiniferatoxin binding measurements. Intracellular Ca²⁺ imaging supports this explanation. IBTU antagonized the elevation in intracellular Ca²⁺ in response to 50 nM capsaicin with an IC₅₀ of 106 ± 35 nM. Likewise, 600 nM IBTU was able to antagonize the elevation in intracellular Ca²⁺ in response to 100 pM resiniferatoxin in the presence of normal (1.8 mM) extracellular Ca²⁺, where the increase in intracellular calcium reflects calcium influx. In contrast, in the absence of extracellular Ca²⁺, where in this system resiniferatoxin induces a modest increase in calcium from intracellular stores, IBTU was unable to block the response to resiniferatoxin, although the TRPV1 antagonist 5-iodoresiniferatoxin was able to do so. In summary, IBTU is a novel, potent TRPV1 antagonist with marked selectivity between subpopulations of TRPV1 and may permit the function of these distinct pools to be explored and potentially exploited.

Address correspondence to: Peter M. Blumberg, Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute, National Institutes of Health, Bldg. 37, Rm. 4048, 37 Convent Dr., MSC 4255, Bethesda, MD 20892-4255. E-mail: blumberp{at}dc37a.nci.nih.gov

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