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Methods and compositions for treating hyperalgesia

A technology for hyperalgesia and compounds, which can be used in drug combinations, pharmaceutical formulations, non-central analgesics, etc., and can solve problems such as unknown molecular identities

Inactive Publication Date: 2009-04-08
IRM +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, unlike nociceptive thermosensation, the molecular identity of the mechanotransduction channels responsible for sensing nociceptive mechanical forces associated with pain remains unknown

Method used

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  • Methods and compositions for treating hyperalgesia
  • Methods and compositions for treating hyperalgesia
  • Methods and compositions for treating hyperalgesia

Examples

Experimental program
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Effect test

Embodiment 1

[0059] Example 1. TRPA1 is a polymorphic receptor for nociceptive mechanical and thermal stimuli

[0060] We tested whether TRPA1 is activated by mechanical force. The electrophysiological behavior of Chinese hamster ovary (CHO) cells expressing thermoTRP was studied in two different mechanical stress-stress application assays using recording pipettes and varying external osmolarity. In whole-cell recordings, TRPA1-expressing cells induced cell contraction [either -100 mmHg suction (n = 10) or application of 450 mOsm hypertonic solution (n = 8)] (Fig. 1A) but not cell swelling [or by Stimulation of +100 mmHg (n=11) or 220 mOsm (n=8)] showed robust current responses. Currents evoked by pressure, hyperosmosis, or cold (n = 62) showed similar desensitization and had similar reversal potentials and rectification properties, suggesting that these mechanosensitive currents result from TRPA1 activation (Fig. 1B). It was also observed that non-transfected control CHO cells and oth...

Embodiment 2

[0063] Example 2. TRPA1 plays an essential role in mechanical pain perception in vivo

[0064] We next tested whether acute blockade of TRPA1 had any physiological consequences on pain perception. RR, Gd 3+ Or camphor is not a specific compound and cannot be used in vivo. Using the FLIPR calcium influx assay, we screened 43,648 small molecules for their ability to block cinnamaldehyde-activation of human TRPA1 in CHO cell lines. Several hits were shown to be structural analogs of cinnamaldehyde. We performed an in-depth analysis of one of these analogues, compound 18, (Z)-4-(4-chlorophenyl)-3-methylbut-3-ene-2-oxime (Maybridge, Cornwall, UK). Compound 18 blocked TRPA1 activation by 50 μM cinnamaldehyde in the CHO cell FLIPR assay, and its IC on human and mouse clones 50 The values ​​were 3.1 μM and 4.5 μM, respectively ( FIG. 3B ). In contrast, compound 18 did not block TRPV1, TRPV3, TRPV4 and TRPM8 at 50 μΜ (data not shown). Compound 18 reduced the EC of cinnamaldehyd...

Embodiment 3

[0066] Example 3. Further evidence for the function of TRPA1 in mechanical and cold hyperalgesia

[0067]To the best of our knowledge, it is not possible to test the noxious cold response in mice. For example, mice show no nociceptive response to hypothermia as low as 0 °C and no cold allodynia in response to CFA. Cold activation of TRPA1 is controversial, but its in vivo role in cold hyperalgesia in rats has recently been proposed (Jordt et al., Nature 427:260, 2004 and Obata et al., J Clin Invest 115:2393, 2005). We therefore explored the role of TRPA1 using compound 18 in rats. We found that rat TRPA1 was also blocked by compound 18, similarly to human and mouse TRPA1 (data not shown). We observed that CFA-induced cold hyperalgesia in rats was potently blocked by Compound 18 in a 5°C dish (Fig. 4C). Taken together, these data suggest that TRPA1 functions as both a cold sensor and a mechanoreceptor in vivo, but only after sensitization with inflammatory or injury signal...

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Abstract

This invention provides compounds which specifically inhibit TRPA1 but not other members of the thermoTRP ion channel family. Also provided in the invention are methods of using TRPA1-specific inhibitors to treat or alleviate pains mediated by noxious mechanosensation.

Description

[0001] Cross References to Related Applications [0002] This patent application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application 60 / 775,519, filed February 21, 2006. The disclosure of this prior application is incorporated herein by reference in its entirety and for all purposes. [0003] Statement Regarding Government Funding [0004] This invention was made in part with government support under NINDS Award Nos. NS42822 and NS046303 awarded by the National Institutes of Health. The US Government may therefore have certain rights in this invention. technical field [0005] The present invention generally relates to methods and compositions for antagonizing ion channels involved in nociceptive chemosensation, thermosensation and mechanosensation. More specifically, the present invention relates to compounds that specifically inhibit mechanotransduction mediated by TRPAl, and methods of using such compounds to treat mechanical hyperalgesia. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/197A61P29/00
CPCA61K31/197A61P25/04A61P29/00A61P43/00
Inventor A·帕塔普蒂安T·J·热格拉
Owner IRM
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