Abstract
The transient receptor potential vanilloid-1 (TRPV1) channel is involved in the development and maintenance of pain and participates in the regulation of temperature. The channel is activated by diverse agents, including capsaicin, noxious heat (≥ 43°C), acidic pH (< 6), and endogenous lipids including N-arachidonoyl dopamine (NADA). Antagonists that block all modes of TRPV1 activation elicit hyperthermia. To identify efficacious TRPV1 antagonists that do not affect temperature antagonists representing multiple TRPV1 pharmacophores were evaluated at recombinant rat and human TRPV1 channels with Ca2+ flux assays, and two classes of antagonists were identified based on their differential ability to inhibit acid activation. Although both classes of antagonists completely blocked capsaicin- and NADA-induced activation of TRPV1, select compounds only partially inhibited activation of the channel by protons. Electrophysiology and calcitonin gene-related peptide release studies confirmed the differential pharmacology of these antagonists at native TRPV1 channels in the rat. Comparison of the in vitro pharmacological properties of these TRPV1 antagonists with their in vivo effects on core body temperature confirms and expands earlier observations that acid-sparing TRPV1 antagonists do not significantly increase core body temperature. Although both classes of compounds elicit equivalent analgesia in a rat model of knee joint pain, the acid-sparing antagonist tested is not effective in a mouse model of bone cancer pain.
Footnotes
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS:
- TRPV1
- transient receptor potential vanilloid-1
- ASIC
- acid-sensing ion channel
- CGRP
- calcitonin gene-related peptide
- DPBS
- Dulbecco's phosphate-buffered saline
- DRG
- dorsal root ganglion
- FLIPR
- fluorometric imaging plate reader
- Fura-2 AM
- Fura-2 acetoxymethyl ester
- GF
- grip force
- HBSS
- Hank's balanced salt solution
- HEK
- human embryonic kidney
- MEM
- minimal essential medium
- MES
- 2-(N-morpholino)ethanesulfonic acid
- MIA
- sodium monoiodoacetate
- NADA
- N-arachidonoyl-dopamine
- OA
- osteoarthritis
- pH50
- pH of half-maximal activation
- SAR
- structure-activity relationship
- ABT-102
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- AMG 517
- N-(4-(6-(4-trifluoromethylphenyl)pyrimidin-4-yloxy)benzothiazol-2-yl)acetamide
- AMG8562
- (R,E)-N-(2-hydroxy-2,3-dihydro-1H-inden-4-yl)-3-(2-(piperidin-1-yl)-4-(trifluoromethyl)phenyl)-acrylamide
- AS1928370
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- 1-(3-methylpyridin-2-yl)-N-(4-(trifluoromethylsulfonyl)phenyl)-1,2,3,6-tetrahydropyridine-4-carboxamide
- A-993610
- (S)-1-(3-chloropyridin-2-yl)-3-methyl-N-(4-(trifluoromethyl)phenyl)-1,2,3,6-tetrahydropyridine-4-carboxamide
- A-1098807
- 1-((R)-6-fluoro-2,2-dimethylchroman-4-yl)-3-((S)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea
- A-1098808
- 1-((R)-6-fluoro-2,2-dimethylchroman-4-yl)-3-((R)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea
- A-1105512
- (R)-1-(2,2-diethyl-6-fluorochroman-4-yl)-3-(isoquinolin-5-yl)urea
- A-1106625
- 1-((R)-7-fluoro-2,2-dimethyl-chroman-4-yl)-3-((S)-7-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl)urea
- A-1153818
- 1-((R)-2,2-diethyl-7-fluorochroman-4-yl)-3-((R)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea
- A-1165442
- (R)-1-(7-chloro-2,2-bis(fluoromethyl)chroman-4-yl)-3-(3-methylisoquinolin-5-yl)urea
- A-1165746
- (R)-1-(8-fluoro-2,2-bis(fluoromethyl)chroman-4-yl)-3-(3-methylisoquinolin-5-yl)urea
- A-1208747
- (R)-1-(2,2-dimethyl-7-(trifluoromethyl)chroman-4-yl)-3-(3-methylisoquinolin-5-yl)urea
- A-1241797
- 1-((2S,4R)-7-chloro-2-(difluoromethyl)-2-methylchroman-4-yl)-3-(3-methylisoquinolin-5-yl)urea
- A-1233371
- 1-((2R,4R)-7-chloro-2-(fluoromethyl)-2-methylchroman-4-yl)-3-(3-methylisoquinolin-5-yl)urea
- A-1233372
- 1-((2S,4R)-7-chloro-2-(fluoromethyl)-2-methylchroman-4-yl)-3-(3-methylisoquinolin-5-yl)urea
- A-1241407
- (R)-1-(7-chloro-2,2-bis(fluoromethyl)chroman-4-yl)-3-(3-methyl-7-(trifluoromethyl)isoquinolin-5-yl)urea.
- Received November 21, 2011.
- Accepted May 7, 2012.
- U.S. Government work not protected by U.S. copyright
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