Silicon Investor (SI) -- The First Internet Community

STOCKTALK

We've detected that you're using an ad content blocking browser plug-in or feature. Ads provide a critical source of revenue to the continued operation of Silicon Investor. We ask that you disable ad blocking while on Silicon Investor in the best interests of our community. If you are not using an ad blocker but are still receiving this message, make sure your browser's tracking protection is set to the 'standard' level.

Biotech / Medical : Neurogen (NRGN) -- Ignore unavailable to you. Want to Upgrade?

To: phbolton who wrote (346)	6/19/2003 11:36:11 PM
From: Miljenko Zuanic	Read Replies (1) \| Respond to of 523

VR1: The Journal of Pharmacology And Experimental Therapeutics Fast Forward First published on April 29, 2003; 10.1124/jpet.102.045674 0022-3565/03/3061-377-386$7.00 JPET 306:377-386, 2003 NEUROPHARMACOLOGY N-(4-Tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine -1(2H)-carbox-amide (BCTC), a Novel, Orally Effective Vanilloid Receptor 1 Antagonist with Analgesic Properties: I. In Vitro Characterization and Pharmacokinetic Properties Kenneth J. Valenzano, Elfrida R. Grant, Gang Wu, Mohamed Hachicha, Lori Schmid, Laykea Tafesse, Qun Sun, Yakov Rotshteyn, Joseph Francis1, James Limberis2, Shiazah Malik1, Edward R. Whittemore3, and Dianne Hodges1 Departments of Molecular Pharmacology (K.J.V., E.R.G., G.W., M.H., L.S.) and Computational, Combinatorial, and Medicinal Chemistry (L.T., Q.S.), Purdue Pharma Discovery Research, Cranbury, New Jersey; and Discovery Support (Y.R.), Purdue Pharma, Ardsley, New York 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.