AG1529
AG1529 is a TRPV1 inhibitor and capsaicinoid-based soft agent with a human TRPV1 IC50 of 0.9-0.93 μM. AG1529 reversibly blocks capsaicin-evoked TRPV1 activation, binds to the TRPV1 capsaicin binding site, moderately affects pH-induced TRPV1 gating, and does not alter voltage- or heat-mediated TRPV1 responses. AG1529 suppresses TRPV1-mediated neuronal excitability, reduces capsaicin- and pH-evoked neuronal firing, abolishes histaminergic and inflammation-mediated TRPV1 sensitization. AG1529 exhibits anti-nociceptive and antipruritic effects, attenuates in vivo hyperalgesia and pruritus, dose-dependently reduces acute histaminergic itch in rodents, and mildly blocks hTRPA1 and hTRPM8 channel activity. AG1529 undergoes hydrolysis and dermal deactivation, minimizes TRPV1-associated side reactions, does not evoke capsaicin-like burning sensation, and does not disrupt physiological thermal regulation. AG1529 can be used for the research of inflammatory cutaneous nociception and acute histaminergic pruritus.
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- No. CAS: 2225980-49-2
- Fòrmula: C22H34INO5
- Peso molecular:519.41
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Almacenamiento:
Please store the product under the recommended conditions in the Certificate of Analysis.
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Actividad biológica
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Chemical Information
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Actividad biológica
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TRPV1 0.93 μM (IC50) |
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Cell Line
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Type | Value | Description | References |
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| SH-SY5Y | IC50 |
0.86 μM
Compound: 37
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Antagonist activity at rat TRPV1 expressed in human SH-SY5Y cells assessed as reduction in capsaicin-induced intracellular calcium accumulation preincubated with cells followed by capsaicin addition by Fluo-4 NW dye based fluorescence assay
Antagonist activity at rat TRPV1 expressed in human SH-SY5Y cells assessed as reduction in capsaicin-induced intracellular calcium accumulation preincubated with cells followed by capsaicin addition by Fluo-4 NW dye based fluorescence assay
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[PMID: 30783490] |
AG1529 (1-100 μM) potently antagonizes TRPV1 in SH-SY5Y cells stably expressing TRPV1 with an IC50 of 0.93 μM[1].
AG1529 is highly stable in HaCaT homogenate (25 μM; 240 min), moderately stable in human plasma (100 μM; 20 min), and completely hydrolyzed in human liver S9 fraction (50 μM; 60 min) under the tested conditions[1].
AG1529 (50 μM; 120 min) is significantly hydrolyzed in primary adult human epidermal keratinocyte and dermal fibroblast homogenates, with only 22.6% and 13.3% residual substrate remaining after 120 min, respectively[1].
AG1529 (0.2 mg/mL) is hydrolyzed by both hCE1 and hCE2, with preferential metabolism by hCE2 as indicated by its higher intrinsic clearance and shorter half-life with this isoform[1].
AG1529 (1 μM) reversibly and competitively blocks capsaicin-activated hTRPV1 in HEK293 cells with an IC50 of 0.9 μM[2].
AG1529 (1-10 μM; 30 s) moderately blocks pH-induced activation of hTRPV1 in HEK293 cells at 10 μM, but does not significantly affect voltage- or heat-mediated hTRPV1 gating at tested concentrations[2].
AG1529 (10 μM; 30 s) moderately inhibits menthol-activated hTRPM8 and AITC-activated hTRPA1 in HEK293 cells at 10 μM, with significantly lower efficacy than its inhibition of hTRPV1[2].
AG1529 binds to the capsaicin binding site of TRPV1 in a conformation similar to capsaicin, supporting its mechanism as a competitive TRPV1 antagonist, while steric hindrance in TRPA1 reduces its binding affinity for that channel[2].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
| Species | Dose | Route | T1/2 | Tmax | Cmax | AUClast | AUCinf |
|---|---|---|---|---|---|---|---|
| Mice[2] | 5 mg/kg | i.v. | 3.6 min | 5.0 min | 738.1 ng/mL | 14709.3 min·ng/mL | 14728.5 min·ng/mL |
AG1529 (1-10 mg/kg; i.v.; single dose) produces a transient, dose-dependent reversal of CFA-induced thermal hyperalgesia without affecting contralateral thermal nociception[1].
AG1529 (100 μg; i.pl.; single dose; 30 minutes prior to histamine) significantly reduces histaminergic pruritus in mice, with peak effects observed 10-20 minutes after histamine injection[1].
AG1529 (100 μg; i.pl.; single dose; 30 minutes prior to chloroquine) significantly reduces non-histaminergic pruritus in mice, with peak effects observed 5-15 minutes after chloroquine injection[1].
AG1529 (10 mg/kg; i.v.; single dose) does not affect body temperature in mice, avoiding the hyperthermia side effect associated with other TRPV1 antagonists[1].
AG1529 (0.1-1% w/v; topical wipe; single application) dose-dependently reduces histamine-induced pruritus in rats, with 1% AG1529 producing the greatest attenuation of scratching behavior[2].
AG1529 (0.1-1% w/w; topical application; twice daily; 3 days) significantly reduces histamine-induced pruritus in rats, with 1% AG1529 completely eliminating scratching behavior[2].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:unspecified[1]
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Dosage:10 μg; 30 μg; 100 μg
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Administration:i.pl.; single dose
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Result:Ablated CFA-induced thermal hyperalgesia in the ipsilateral paw in a dose-dependent and transient manner.
Showed anti-hyperalgesic activity at 30 minutes, peaked at 60 minutes, and lasted for 90 minutes at the 100 μg dose.
Did not affect thermal nociception in the contralateral paw.
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Animal Model:unspecified[1]
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Dosage:1 mg/kg; 3 mg/kg; 10 mg/kg
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Administration:i.v.; single dose
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Result:Attenuated CFA-induced thermal hyperalgesia in the ipsilateral paw in a dose-dependent and transient manner.
Showed anti-hyperalgesic effects at 30 minutes, lasting 60 minutes at the 1 mg/kg dose.
Showed effects at 60 minutes, lasting 90 minutes at the 3 mg/kg dose.
Showed significant effects only at 60 minutes at the 10 mg/kg dose.
Did not affect thermal nociception in the contralateral paw.
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Animal Model:unspecified[1]
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Dosage:100 μg
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Administration:i.pl.; single dose; 30 minutes prior to histamine
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Result:Attenuated histamine-induced paw licking time, with statistically significant reductions in the 10-15 minute and 15-20 minute intervals after histamine instillation.
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Animal Model:unspecified[1]
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Dosage:100 μg
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Administration:i.pl.; single dose; 30 minutes prior to chloroquine
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Result:Reduced chloroquine-induced paw licking time, with statistically significant reductions in the 5-10 minute and 10-15 minute intervals after chloroquine instillation.
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Animal Model:unspecified[1]
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Dosage:10 mg/kg
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Administration:i.v.; single dose
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Result:Did not alter mouse body temperature over the 120-minute observation period, unlike the positive control TRPV1 antagonist BCTC which induced significant hyperthermia.
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Animal Model:Wistar (adult, 100-125 g, pruritus model via subcutaneous histamine injection)[2]
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Dosage:0.1% w/v; 1% w/v
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Administration:topical wipe; single application
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Result:Significantly reduced histamine-induced licking time across all 10-minute intervals from 0-60 minutes post-histamine injection.
Produced a dose-dependent reduction in total scratching counts over 60 minutes: 0.1% AG1529 reduced scratching compared to vehicle (p = 0.0003), and 1% AG1529 produced an even greater reduction (p < 0.0001 vs vehicle; p = 0.0395 vs 0.1% AG1529).
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Animal Model:Wistar (adult, 100-125 g, pruritus model via subcutaneous histamine injection)[2]
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Dosage:0.1% w/w; 1% w/w
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Administration:topical application; twice daily; 3 days
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Result:Significantly reduced histamine-induced licking time across all 10-minute intervals from 0-60 minutes post-histamine injection, with the 1% dose nearly eliminating licking activity in most intervals.
Reduced total scratching counts over 60 minutes: 0.1% AG1529 reduced scratching compared to vehicle (p = 0.0122), and 1% AG1529 fully abrogated scratching behavior (p = 0.0003 vs vehicle).
Chemical Information
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No. CAS 2225980-49-2
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Peso molecular 519.41
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Fòrmula C22H34INO5
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SMILES
O=C(CCCCCCCCCCC)OCC(NCC1=C(I)C=C(O)C(OC)=C1)=O
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Envío
Room temperature in continental US; may vary elsewhere.
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Almacenamiento
Please store the product under the recommended conditions in the Certificate of Analysis.
Pureza y Documentación
Referencias
[1]. Serafini M, et al. Targeting Transient Receptor Potential Vanilloid 1 (TRPV1) Channel Softly: The Discovery of Passerini Adducts as a Topical Treatment for Inflammatory Skin Disorders. J Med Chem. 2018;61(10):4436-4455. [Content Brief]
[2]. Nikolaeva-Koleva M, et al. A capsaicinoid-based soft drug, AG1529, for attenuating TRPV1-mediated histaminergic and inflammatory sensory neuron excitability. Sci Rep. 2021;11(1):246. Published 2021 Jan 8. [Content Brief]
Calculators
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