A 967079

A-967079 is an antagonist of transient receptor potential A1 (TRPA1) receptor with IC50 values of 289 nM and 67 nM at rat and human TRPA1 receptors, respectively [1].

There is a larger family of transient receptor potential (TRP) ion channels. In this family, there are TRPV, TRPM, TRPC, TRPN, TRPP and TRPML. TRPA1 is a part of this family and is expressed in small and medium-sized peptidergic primary afferent sensory neurons that also express TRPV1 [1].

Treatment with A-967079 attenuated Ca2+ signal in WT TG neurons and resulted in a further reduction in Trpv4-/- TG neurons in response to formalin. Treatment with A-967079 reduced the percentage of responsive cells from 27.7% to 15.8% when acutely blocking TRPA1 and to a mere 3.2% in Trpv4-/- TG neurons plus TRPA1 inhibitor [2].

Spontaneous activity of WDR neurons can indicate central sensitization and possibly non-evoked or ongoing pain. In uninjured and CFA-inflamed rats, systemic injection of A-967079 at 30 μmol/kg, i.v. made responses of wide dynamic range (WDR) and nociceptive specific (NS) neurons decrease, following noxious pinch stimulation of the ipsilateral hind paw. Similarly in both OA and OA-sham rats, A-967079 decreased the responses of WDR neurons to high-intensity mechanical stimulation of the knee joint. Administration with A-967079 also reduced WDR neuronal responses to low-intensity mechanical stimulation (10 g von Frey hair) in CFA-inflamed rats, but not in uninjured rats. Additionally, A-967079 injection decreased the spontaneous activity of WDR neurons in CFA-inflamed rats, but not in uninjured, OA, and OA-sham animals [1].

References:
[1].  McGaraughty S, Chu KL, Perner RJ, et al. TRPA1 modulation of spontaneous and mechanically evoked firing of spinal neurons in uninjured, osteoarthritic, and inflamed rats. Molecular pain, 2010, 6(1): 1.
[2].  Chen Y, Kanju P, Fang Q, et al. TRPV4 is necessary for trigeminal irritant pain and functions as a cellular formalin receptor. PAIN, 2014, 155(12): 2662-2672.

Selective blockade of TRPA1 channel attenuates pathological pain without altering noxious cold sensation or body temperature regulation.[Pubmed:21402443]

Pain. 2011 May;152(5):1165-72.

Despite the increasing interest in TRPA1 channel as a pain target, its role in cold sensation and body temperature regulation is not clear; the efficacy and particularly side effects resulting from channel blockade remain poorly understood. Here we use a potent, selective, and bioavailable antagonist to address these issues. A-967079 potently blocks human (IC(50): 51 nmol/L, electrophysiology, 67 nmol/L, Ca(2+) assay) and rat TRPA1 (IC(50): 101 nmol/L, electrophysiology, 289 nmol/L, Ca(2+) assay). It is >1000-fold selective over other TRP channels, and is >150-fold selective over 75 other ion channels, enzymes, and G-protein-coupled receptors. Oral dosing of A-967079 produces robust drug exposure in rodents, and exhibits analgesic efficacy in allyl isothiocyanate-induced nocifensive response and osteoarthritic pain in rats (ED(50): 23.2 mg/kg, p.o.). A-967079 attenuates cold allodynia produced by nerve injury but does not alter noxious cold sensation in naive animals, suggesting distinct roles of TRPA1 in physiological and pathological states. Unlike TRPV1 antagonists, A-967079 does not alter body temperature. It also does not produce locomotor or cardiovascular side effects. Collectively, these data provide novel insights into TRPA1 function and suggest that the selective TRPA1 blockade may present a viable strategy for alleviating pain without untoward side effects.

TRPA1 modulation of spontaneous and mechanically evoked firing of spinal neurons in uninjured, osteoarthritic, and inflamed rats.[Pubmed:20205719]

Mol Pain. 2010 Mar 5;6:14.

BACKGROUND: There is growing evidence supporting a role for TRPA1 receptors in the neurotransmission of peripheral mechanical stimulation. In order to enhance understanding of TRPA1 contributions to mechanotransmission, we examined the effects a selective TRPA1 receptor antagonist, A-967079, on spinal neuronal activity following peripheral mechanical stimulation in uninjured, CFA-inflamed, and osteoarthritc (OA) rats. RESULTS: Systemic injection of A-967079 (30 micromol/kg, i.v.) decreased the responses of wide dynamic range (WDR), and nociceptive specific (NS) neurons following noxious pinch stimulation of the ipsilateral hind paw in uninjured and CFA-inflamed rats. Similarly, A-967079 reduced the responses of WDR neurons to high-intensity mechanical stimulation (300 g von Frey hair) of the knee joint in both OA and OA-sham rats. WDR neuronal responses to low-intensity mechanical stimulation (10 g von Frey hair) were also reduced by A-967079 administration to CFA-inflamed rats, but no effect was observed in uninjured rats. Additionally, the spontaneous activity of WDR neurons was decreased after A-967079 injection in CFA-inflamed rats but was unaltered in uninjured, OA, and OA-sham animals. CONCLUSIONS: Blockade of TRPA1 receptors disrupts transmission of high-intensity mechanical stimulation to the spinal cord in both uninjured and injured rats indicating that TRPA1 receptors have an important role in noxious mechanosensation in both normal and pathological conditions. TRPA1 receptors also contribute to the transmission of low-intensity mechanical stimulation, and to the modulation of spontaneous WDR firing, but only after an inflammatory injury.

A-967079 is a selective TRPA1 receptor antagonist with IC50s of 67 nM and 289 nM at human and rat TRPA1 receptors, respectively, and has good penetration into the CNS.

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