Abstract
TRPV1, a member of the transient receptor potential (TRP) family, is a nonselective calcium permeable ion channel gated by physical and chemical stimuli. In the skin, TRPV1 plays an important role in neurogenic inflammation, pain and pruritus associated to many dermatological diseases. Consequently, TRPV1 modulators could represent pharmacological tools to respond to important patient needs that still represent an unmet medical demand. Previously, we reported the design of capsaicinoid-based molecules that undergo dermal deactivation (soft drugs), thus preventing their long-term dermal accumulation. Here, we investigated the pharmacological properties of the lead antagonist, 2-((4-hydroxy-2-iodo-5-methoxybenzyl) amino)-2-oxoethyl dodecanoate (AG1529), on heterologously expressed human TRPV1 (hTRPV1), on nociceptor excitability and on an in vivo model of acute pruritus. We report that AG1529 competitively blocked capsaicin-evoked activation of hTRPV1 with micromolar potency, moderately affected pH-induced gating, and did not alter voltage- and heat-mediated responses. AG1529 displays modest receptor selectivity as it mildly blocked recombinant hTRPA1 and hTRPM8 channels. In primary cultures of rat dorsal root ganglion (DRG) neurons, AG1529 potently reduced capsaicin-evoked neuronal firing. AG1529 exhibited lower potency on pH-evoked TRPV1 firing, and TRPA1-elicited nociceptor excitability. Furthermore, AG1529 abolished histaminergic and inflammation mediated TRPV1 sensitization in primary cultures of DRG neurons. Noteworthy, dermal wiping of AG1529, either in an acetone-based formulation or in an anhydrous ointment, dose-dependently attenuated acute histaminergic itch in a rodent model. This cutaneous anti-pruritic effect was devoid of the normal nocifensive action evoked by the burning sensation of capsaicin. Taken together, these preclinical results unveil the mode of action of AG1529 on TRPV1 channels and substantiate the tenet that this capsaicinoid-based soft drug is a promising candidate for drug development as a topical anti-pruritic and anti-inflammatory medication.
Highlights
Transient receptor potential vanilloid channel (TRPV1) is a thermally activated ion channel that plays a pivotal role in thermosensation, in the detection of environmental noxious temperatures (> 42 °C)[1,2]
The same paradigm applied to cells that were exposed to 1 μM AG1529 during the first capsaicin pulse, resulted in an increment of the second capsaicin response (Fig. 1D, bottom trace; and Fig. 1E; P2/ P1 = 1.30 ± 0.09 (n = 5), p = 0.0027, AG1529 vs. control, unpaired, two-tail, t-student). These data are consistent with: (i) a reversible blockade of human TRPV1 ortholog (hTRPV1) by AG1529; and, (ii) a partial inhibition of capsaicin-induced TRPV1 tachyphylaxis by AG1519. These findings indicate that AG1529 is a reversible blocker, and further suggest that it acts as a competitive capsaicin antagonist of hTRPV1
We reported the design of soft drugs based on the capsaicinoid scaffold as TRPV1 antagonists that neither show the burning nocifensive response in animals, nor alter the body temperature[31]
Summary
Transient receptor potential vanilloid channel (TRPV1) is a thermally activated ion channel that plays a pivotal role in thermosensation, in the detection of environmental noxious temperatures (> 42 °C)[1,2]. Cutaneous TRPV1 channels are end targets for inflammatory and pruritogenic agents[17,18,19] These agents activate intracellular signalling pathways that converge onto TRPV1, increasing its g ating[20] and/or promoting the surface expression of c hannels[21]. Our capsaicinoid antagonists preserve the pharmacological scaffold of the vanilloid group, but are devoid of the burning sensation associated with capsaicin. Compound AG1529 was selected as a promising candidate for further development due to its in vivo therapeutic activity in animal models of inflammatory pain and p ruritus[31]. Our data suggest that AG1529 acts as a competitive capsaicin antagonist This compound modestly blocks pH-evoked hTRPV1 gating but not voltage and temperature activation. Our preclinical results suggest that AG1529 is a good candidate for development as an anti-inflammatory and anti-pruritic drug associated to cutaneous disorders
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