Transient Receptor Potential Ankyrin 1 (TRPA1) receptor (antagonist; IC₅₀ = 67 nM at human TRPA1; IC₅₀ = 289 nM at rat TRPA1) [1]

A-967079 is a selective TRPA1 receptor antagonist. At a concentration of 10 μM, it was weak (EC₅₀ > 5 μM) or not active at 89 different G-protein-coupled receptors, enzymes, transporters, and ion channels, including other TRP channels, confirming its selectivity. [1]

In Freund's adjuvant (CFA) neuronal response, systemic injection of A-967079 (30 μMol/kg, i.v.) lowers nociceptive jumping (NS) and wide dynamic range (WDR) following painful crushing of the undamaged and inflamed ipsilateral hind paw. A-967079 (30 μMol/kg, i.v.) administration in CFA-inflamed WT significantly decreased the response to destructive simulated stimulation of WDR neurons compared with baseline derivation (p=0.0013, repeated-measures seismic analysis), Kazakhstan (p=0.0001, coronary artery analysis), and other WT. This effect was similar to that seen in uninjured WT. Thirty-five minutes after injection, the highest ratio bearing level influence on inflammatory simulated-evoked activity was seen. Additionally noteworthy when compared to unimpaired correlations (repeated measures and limb coronal analyses, respectively) were injections of A-967079 into the CFA that were connected to inflammation. reduced WDR neurons' responsiveness to 10-g von Frey stimulation (p=0.0004 and p=0.0001). Thus, at the axial level (35 minutes after injection), the maximum observed reduction in von Frey-evoked activity was 67.69 ± 18.39%, which is similar to the effect of A-967079 on inflammatory stimulus-evoked activity [1].

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In uninjured rats: Systemic administration of A-967079 (30 μmol/kg, i.v.) significantly reduced the responses of spinal wide dynamic range (WDR) and nociceptive specific (NS) neurons to noxious pinch stimulation of the ipsilateral hind paw. WDR responses to pinch were reduced by approximately 30% from baseline. The drug had no effect on WDR responses to low-intensity (10 g von Frey) mechanical stimulation or on the spontaneous firing of WDR neurons. [1]
In Complete Freund's Adjuvant (CFA)-inflamed rats: A-967079 (30 μmol/kg, i.v.) significantly reduced WDR neuronal responses to both noxious pinch (max. 61% decrease) and low-intensity (10 g von Frey) mechanical stimulation (max. 68% decrease). It also significantly attenuated the elevated spontaneous firing of WDR neurons (max. 59% decrease). The drug also nearly eliminated NS neuronal responses to noxious pinch (max. 92% decrease). [1]
In osteoarthritic (OA) and OA-sham rats: A-967079 (30 μmol/kg, i.v.) significantly reduced the responses of WDR neurons to high-intensity (300 g von Frey) mechanical stimulation of the knee joint (max. 43-47% decrease). It did not alter the spontaneous firing of WDR neurons in these models. [1]

Electrophysiology Studies:** Male Sprague-Dawley rats (uninjured, CFA-inflamed, OA, or OA-sham) were anesthetized with pentobarbital and maintained on a propofol infusion. Catheters were placed in the jugular veins for drug administration. A laminectomy was performed to expose the spinal cord (T12-L3 for hind paw input; T9-L2 for knee input). Extracellular recordings were made from WDR and NS neurons in the dorsal horn using platinum-iridium microelectrodes. After characterizing the neuron's receptive field and response properties, three baseline responses to a specific mechanical stimulus (10 g or 300 g von Frey hair, or noxious pinch with a bulldog clamp) were recorded. A-967079 (30 μmol/kg) or vehicle (polyethylene glycol) was then administered intravenously over 6-7 minutes. Spontaneous and evoked neuronal activity were measured at 5, 15, 25, and 35 minutes post-injection. [1]

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Electrophysiology Studies: Male Sprague-Dawley rats (uninjured, CFA-inflamed, OA, or OA-sham) were anesthetized with pentobarbital and maintained on a propofol infusion. Catheters were placed in the jugular veins for drug administration. A laminectomy was performed to expose the spinal cord (T12-L3 for hind paw input; T9-L2 for knee input). Extracellular recordings were made from WDR and NS neurons in the dorsal horn using platinum-iridium microelectrodes. After characterizing the neuron's receptive field and response properties, three baseline responses to a specific mechanical stimulus (10 g or 300 g von Frey hair, or noxious pinch with a bulldog clamp) were recorded. A-967079 (30 μmol/kg) or vehicle (polyethylene glycol) was then administered intravenously over 6-7 minutes. Spontaneous and evoked neuronal activity were measured at 5, 15, 25, and 35 minutes post-injection. [1]

A-967079 has good penetration into the central nervous system (CNS). [1]
The intravenous dose of 30 μmol/kg was selected based on extrapolated plasma levels that were effective in behavioral studies. [1]

[1]. TRPA1 modulation of spontaneous and mechanically evoked firing of spinal neurons in uninjured, osteoarthritic, and inflamed rats. Mol Pain. 2010 Mar 5;6:14.

See also: A-967079 (Note has been moved to).

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A-967079 is a potent and selective small molecule antagonist of the TRPA1 ion channel. It was synthesized and characterized at Abbott Laboratories. [1]
This study demonstrates that A-967079 is a useful pharmacological tool to investigate the role of TRPA1 in mechanotransmission and pain signaling in vivo. [1]
The results show that TRPA1 receptors contribute to the transmission of high-intensity (noxious) mechanical signals to the spinal cord under both normal and pathological (inflammation, osteoarthritis) conditions. Following inflammatory injury (CFA), TRPA1 also contributes to the transmission of low-intensity (non-noxious) mechanical signals and to the heightened spontaneous activity of spinal neurons, which may correlate with ongoing or "unevoked" pain. [1]
The differential effect of A-967079 on spontaneous firing in CFA versus OA models suggests that inflammation may be a key factor in enhancing TRPA1's contribution to ongoing pain states. [1]

207.105

1170613-55-4

1170613-55-4

60150207

White to off-white solid powder

1.0±0.1 g/cm3

324.4±34.0 °C at 760 mmHg

150.0±25.7 °C

0.0±0.7 mmHg at 25°C

1.498

3.73

1

3

3

15

252

0

FC1C([H])=C([H])C(=C([H])C=1[H])/C(/[H])=C(/C([H])([H])[H])\C(\C([H])([H])C([H])([H])[H])=N\O[H]

HKROEBDHHKMNBZ-CHBKHGQFSA-N

InChI=1S/C12H14FNO/c1-3-12(14-15)9(2)8-10-4-6-11(13)7-5-10/h4-8,15H,3H2,1-2H3/b9-8+,14-12+

(1E,3E)-1-(4-Fluorophenyl)-2-methyl-1-penten-3-one oxime

A-967079A967079A 967079

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~482.53 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (12.06 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (12.06 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)