Abstract
Vanilloids such as capsaicin have algesic properties and seem to mediate their effects via activation of the vanilloid receptor 1 (VR1), a ligand-gated ion channel highly expressed on primary nociceptors. Although blockade of capsaicin-induced VR1 activation has been demonstrated in vitro and in vivo with the antagonist capsazepine, efficacy in rat models of chronic pain has not been observed with this compound. Here, we describe the in vitro pharmacology of a highly potent VR1 antagonist, N-(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carbox-amide (BCTC). Similar to capsazepine, this compound inhibits capsaicin-induced activation of rat VR1 with an IC50 value of 35 nM. Interestingly however, BCTC also potently inhibits acid-induced activation of rat VR1 (IC50 value of 6.0 nM), whereas capsazepine is inactive. Similarly, in the rat skin-nerve preparation both BCTC and capsazepine block capsaicin-induced activation, whereas the response to acidification is inhibited by BCTC, but not by capsazepine. Specificity for VR1 was demonstrated against 63 other receptor, enzyme, transporter, and ion channel targets. BCTC was orally bioavailable in the rat, demonstrating a plasma half-life of ∼1 h and significant penetration into the central nervous system. Thus, BCTC is a high potency, selective VR1 antagonist that, unlike capsazepine, has potent blocking effects on low pH-induced activation of rat VR1. These properties make it a more suitable candidate than capsazepine for testing the role played by VR1 in rat models of human disease.
Footnotes
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DOI: 10.1124/jpet.102.045674.
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ABBREVIATIONS: CNS, central nervous system; VR1, vanilloid receptor 1; BCTC, N-(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carbox-amide; RT, reverse transcription; PCR, polymerase chain reaction; HEK, human embryonic kidney; FLIPR, fluorescent imaging plate reader; SIF, synthetic interstitial fluid; GTPγS, guanosine 5′-O-(3-thio)triphosphate; ASIC, acid-sensing ion channel.
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↵1 Current address: Allergan, Inc., 2525 Dupont Dr., Irvine, CA 92612.
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↵2 Current address: Pharmacia Corporation, 4901 Searle Pkwy., Skokie, IL 60077.
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↵3 Current address: Vertex Pharmaceuticals LLC, 11010 Torreyana Rd., San Diego, CA 92121.
- Received January 3, 2003.
- Accepted April 15, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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