A 80426
A 80426 is an orally active serotonin (5-HT uptake) inhibitor (IC50 = 13 nM; Ki = 3.8 nM) and α2-Adrenoceptor receptor antagonist (Ki = 2 nM). A 80426 shows weak antagonistic effect to dopamine D1 receptor (Ki = 744 nM) and D2 receptor (Ki = 52 nM). A 80426 upregulates the expression and activity of TRPV1, activates the NF-κB and PI3K pathways, and reduces the levels of pro-inflammatory cytokines IL-1β, IL-6, and TNF-α. A 80426 can be used in research related to inflammatory pain and depression.
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- CAS No.: 152148-63-5
- Formule: C23H27NO2
- Masse moléculaire:349.47
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Activité biologique
Description
A 80426 is an orally active serotonin (5-HT uptake) inhibitor (IC50 = 13 nM; Ki = 3.8 nM) and α2-Adrenoceptor receptor antagonist (Ki = 2 nM). A 80426 shows weak antagonistic effect to dopamine D1 receptor (Ki = 744 nM) and D2 receptor (Ki = 52 nM). A 80426 upregulates the expression and activity of TRPV1, activates the NF-κB and PI3K pathways, and reduces the levels of pro-inflammatory cytokines IL-1β, IL-6, and TNF-α. A 80426 can be used in research related to inflammatory pain and depression[1][2].
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Serotonin 3.8 nM (Ki) |
α2-adrenergic receptor 2 nM (Ki) |
D1 Receptor 744 nM (Ki) |
D2 Receptor 52 nM (Ki) |
TRPV1 |
IL-1β |
IL-6 |
In Vitro
A 80426 potently binds to serotonin uptake sites (Ki = 3.8 nM) and α2-adrenoceptors (Ki = 2.0 nM), and weakly binds to dopamine D1 (Ki = 744 nM) and D2 (Ki = 52 nM) receptors in cell-free radioligand binding assays[2].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
In Vivo
A 80426 (10 mg/kg; i.p.; once daily for 2 consecutive days) exerts analgesic and anti-inflammatory effects in the CFA (HY-153808)-induced inflammatory pain model of C57BL/6 mice[1].
A 80426 (10 mg/kg; i.p.; once daily; for 2 consecutive days) exerts no analgesic or anti-inflammatory effects in the CFA-induced inflammatory pain model of TRPV1-/- mice, confirming that its activity is dependent on TRPV1[1].
A 80426 (0.3-30 μmol/kg; p.o.; single dose; 0.3-10 μmol/kg; p.o.; once daily; for 14 consecutive days) blocks serotonin-mediated PCA-induced hyperactivity in rats, with subchronic administration (ED50 = 4.1 μmol/kg) being more potent than acute oral administration (ED50 = 13 μmol/kg); at oral doses of 6.7 and 22 μmol/kg, the pharmacodynamic effect lasts up to 12 hours[2].
A 80426 (6.7-224 μmoles/kg; i.p.; single administration) does not block Clonidine (HY-12721)-induced hypothermia or reduced locomotor activity in mice when administered i.p. at doses up to 224 μmol/kg, but enhances clonidine-induced hypothermia at i.p. doses of 6.7, 22 and 67 μmol/kg[2].
A 80426 (60-300 μmol/kg; p.o.; single administration) acts as a weak in vivo α2-adrenergic receptor antagonist in rats. An oral dose of 300 μmol/kg is required to produce a mydriatic response shift similar to that induced by an oral dose of 100 μmol/kg Rauwolscine (HY-12710), and its pKB value is 4.40[2].
A 80426 (0.3-30 μmol/kg; p.o.; single administration; 2.2-6.7 μmol/kg; p.o.; once daily; for 5 consecutive days) reverses passive avoidance deficits in olfactory bulbectomized rats, with an acute ED70 of 7.1 μmol/kg for oral administration, and remains effective after once-daily oral administration at doses of 2.2 and 6.7 μmol/kg for 5 consecutive days[2].
A 80426 (6.7-22 μmol/kg; i.p.; single administration; 22 μmol/kg; i.p.; once daily for 3 consecutive days) dose-dependently reduces food intake after acute administration in obese Zucker rats; under the condition of 3 consecutive days of administration, it decreases 24-hour food intake by 15%-20%[2].
A 80426 (100-300 μmol/kg; p.o.; single administration; 6.7-67 μmol/kg; i.v.; cumulative administration every 30 minutes) causes mild, dose-dependent hypotension and transient bradycardia in conscious normotensive rats at oral doses of 100 and 300 μmol/kg, while only transient bradycardia without significant blood pressure changes occurs at intravenous doses up to 67 μmol/kg[2].
A 80426 (10 mg/kg; i.p.; once daily; for 2 consecutive days) exerts no analgesic or anti-inflammatory effects in the CFA-induced inflammatory pain model of TRPV1-/- mice, confirming that its activity is dependent on TRPV1[1].
A 80426 (0.3-30 μmol/kg; p.o.; single dose; 0.3-10 μmol/kg; p.o.; once daily; for 14 consecutive days) blocks serotonin-mediated PCA-induced hyperactivity in rats, with subchronic administration (ED50 = 4.1 μmol/kg) being more potent than acute oral administration (ED50 = 13 μmol/kg); at oral doses of 6.7 and 22 μmol/kg, the pharmacodynamic effect lasts up to 12 hours[2].
A 80426 (6.7-224 μmoles/kg; i.p.; single administration) does not block Clonidine (HY-12721)-induced hypothermia or reduced locomotor activity in mice when administered i.p. at doses up to 224 μmol/kg, but enhances clonidine-induced hypothermia at i.p. doses of 6.7, 22 and 67 μmol/kg[2].
A 80426 (60-300 μmol/kg; p.o.; single administration) acts as a weak in vivo α2-adrenergic receptor antagonist in rats. An oral dose of 300 μmol/kg is required to produce a mydriatic response shift similar to that induced by an oral dose of 100 μmol/kg Rauwolscine (HY-12710), and its pKB value is 4.40[2].
A 80426 (0.3-30 μmol/kg; p.o.; single administration; 2.2-6.7 μmol/kg; p.o.; once daily; for 5 consecutive days) reverses passive avoidance deficits in olfactory bulbectomized rats, with an acute ED70 of 7.1 μmol/kg for oral administration, and remains effective after once-daily oral administration at doses of 2.2 and 6.7 μmol/kg for 5 consecutive days[2].
A 80426 (6.7-22 μmol/kg; i.p.; single administration; 22 μmol/kg; i.p.; once daily for 3 consecutive days) dose-dependently reduces food intake after acute administration in obese Zucker rats; under the condition of 3 consecutive days of administration, it decreases 24-hour food intake by 15%-20%[2].
A 80426 (100-300 μmol/kg; p.o.; single administration; 6.7-67 μmol/kg; i.v.; cumulative administration every 30 minutes) causes mild, dose-dependent hypotension and transient bradycardia in conscious normotensive rats at oral doses of 100 and 300 μmol/kg, while only transient bradycardia without significant blood pressure changes occurs at intravenous doses up to 67 μmol/kg[2].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:C57BL/6 (male, 8-12 weeks old, ~25g, CFA-induced intraplantar inflammatory reactions)[1]
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Dosage:10 mg/kg
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Administration:i.p.; daily; 2 days
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Result:Reduced abdominal withdrawal reflex scores to 1.11.
Increased mechanical withdrawal threshold to 18.1 g.
Increased thermal withdrawal latency to 13.3 s.
Downregulated IL-1β to 226.4%, IL-6 to 189.7%, and TNF-α to 365.9% in DRG and SCDH.
Reversed CFA-induced downregulation of TRPV1 mRNA/protein expression.
Increased CGRP levels.
Increased NFκB p65 mRNA to 125.6%, PI3K mRNA to 110%, and AKT mRNA to 180%.
Increased phosphorylation of NFκB and AKT.
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Animal Model:TRPV1-/- (on C57BL/6 background, 8-12 weeks old, ~25g, CFA-induced intraplantar inflammatory reactions)[1]
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Dosage:10 mg/kg
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Administration:i.p.; daily; 2 days
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Result:Did not significantly alter abdominal withdrawal reflex scores.
Did not significantly alter mechanical withdrawal threshold.
Did not significantly alter thermal withdrawal latency.
Failed to downregulate mRNA or protein levels of IL-1β, IL-6, or TNF-α.
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Animal Model:C57BL/6 (male, 8-12 weeks old, ~25g, CFA-induced intraplantar inflammatory reactions with TRPV1 inhibition)[1]
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Dosage:10 mg/kg
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Administration:i.p.; daily; 2 days
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Result:Increased abdominal withdrawal reflex scores to 2.36 when co-administered with SB-705498.
Decreased mechanical withdrawal threshold to 13.8 g when co-administered with SB-705498.
Decreased thermal withdrawal latency to 11.2 s when co-administered with SB-705498.
Reversed A 80426-induced downregulation of pro-inflammatory cytokines and activation of NFκB, PI3K, and AKT, with NFκB p65 mRNA decreasing to 31.0%.
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Animal Model:Rj:WISTAR (AF) (80-100 g for acute dosing; 100-140 g for duration of action; 140-180 g for subchronic dosing)[2]
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Dosage:0.3-30 μmol/kg (acute and duration of action); 0.3-10 μmol/kg (subchronic)
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Administration:p.o.; single dose (acute and duration of action); once daily; 14 days (subchronic)
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Result:Significantly reduced PCA-induced hyperactivity at 6.7, 10, 22, 30 μmol/kg with an ED50 of 13 μmol/kg, p.o. (acute dosing).
Significantly blocked PCA-induced hyperactivity for at least 12 hours at 6.7 and 22 μmol/kg.
Significantly reduced PCA-induced hyperactivity at 1.0, 3.0, 10 μmol/kg with an ED50 of 4.1 μmol/kg, p.o. (subchronic dosing).
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Animal Model:Rj:NMRI[2]
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Dosage:6.7, 22, 67 and 224 μmol/kg (hypothermia); 6.7, 22 and 67 μmol/kg (hypoactivity)
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Administration:i.p.; single dose
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Result:Failed to block clonidine-induced hypothermia at all tested doses.
Enhanced Clonidine-induced hypothermia at 6.7, 22, and 67 μmol/kg; did not enhance the effect at 224 μmol/kg.
Failed to block clonidine-induced hypoactivity at 6.7, 22, and 67 μmol/kg.
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Animal Model:Rat (225-250 g; anesthetized with pentobarbital)[2]
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Dosage:60-300 μmol/kg
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Administration:p.o.; single dose
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Result:Produced a shift in the Clonidine-induced mydriasis dose-response curve nearly equivalent to 100 μmol/kg, p.o., of Rauwolscine at 300 μmol/kg, p.o., with a mean pK_B of 4.40.
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Animal Model:Sprague-Dawley (330-500 g for acute dosing; 390-560 g for subchronic dosing; bilaterally olfactory bulbectomized)[2]
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Dosage:0.3-30 μmol/kg (acute); 2.2, 6.7 μmol/kg (subchronic)
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Administration:p.o.; single dose (acute); once daily; 5 days (subchronic)
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Result:Significantly reversed the passive avoidance deficit at 2.2, 3.0, 6.7, 10, 22, 30 μmol/kg with an ED70 of 7.1 μmol/kg, p.o. (acute dosing).
Significantly reversed the passive avoidance deficit at 2.2 and 6.7 μmol/kg (subchronic dosing).
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Animal Model:Female obese Zucker (300-450 g)[2]
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Dosage:6.7, 14 and 22 μmol/kg (acute); 22 μmol/kg (subchronic)
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Administration:i.p.; single dose (acute); once daily; 3 days (subchronic)
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Result:Dose-dependently reduced 1-hour food intake in free-fed rats to 38%, 27%, and 6% of control at 6.7, 14, and 22 μmol/kg, respectively.
Reduced food intake in 24-hour fasted rats, with most inhibition occurring in the first hour.
Reduced 24-hour food intake by 15-20% and attenuated weight gain during subchronic dosing, with no rebound over-feeding after dosing.
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Animal Model:Rat (300-350 g; conscious; surgically catheterized)[2]
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Dosage:100, 300 μmol/kg (p.o.); 6.7, 22 and 67 μmol/kg (i.v.)
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Administration:p.o.; single dose; i.v.; cumulative doses at 30-minute intervals
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Result:Reduced blood pressure by less than 10% with minimal heart rate effects at 100 μmol/kg, p.o.
Reduced blood pressure by less than 20% and caused a 30% bradycardia that resolved within 6 hours at 300 μmol/kg, p.o.
Caused transient, dose-dependent bradycardia lasting 30-60 minutes at the highest intravenous dose, with minimal effects on blood pressure at all cumulative intravenous doses.
Chemical Information
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CAS No. 152148-63-5
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Masse moléculaire 349.47
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Formule C23H27NO2
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SMILES
C(N(CCC=1C=C2C(=CC1)C=CO2)C)[C@H]3C=4C(=C(OC)C=CC4)CCC3
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Livraison
Room temperature in continental US; may vary elsewhere.
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Stockage
Please store the product under the recommended conditions in the Certificate of Analysis.
Pureté et documentation
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A 80426 Related Classifications
HY-120037 Related Classifications
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