Cyclazosin
Cyclazosin is an α1D-adrenergic receptor antagonist and a partial agonist of CXCR4/ACKR3. The pKi values of Cyclazosin for cloned human α1D, α1B and α1A adrenergic receptors are 9.28, 9.23 and 8.18, respectively. Cyclazosin induces β-arrestin recruitment in CXCR4 and ACKR3 with EC50 values of 16 μM and 10 μM, respectively, stimulates ERK1/2 phosphorylation, and induces receptor internalization. Cyclazosin potently inhibits CXCL12-induced chemotaxis of primary human aortic vascular smooth muscle cells. Cyclazosin alters MDMA-induced thermoregulatory responses in mice, converting monophasic hyperthermia to a biphasic pattern without affecting resting core body temperature. Cyclazosin can be used for diseases related to tumor metastasis, MDMA-induced hyperthermia and vasoconstriction.
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- CAS No.: 139953-73-4
- Formule: C23H27N5O4
- Masse moléculaire:437.49
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Stockage:
Please store the product under the recommended conditions in the Certificate of Analysis.
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Activité biologique
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Chemical Information
- Pureté et documentation
- Références
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Activité biologique
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Alpha-1A adrenergic receptor 8.18 (pKi) |
Alpha-1A adrenergic receptor 9.23 (pKi) |
Alpha-1D adrenergic receptor 9.28 (pKi) |
CXCR3 10 μM (EC50) |
CXCR4 16 μM (IC50) |
ERK1 |
ERK2 |
Cyclazosin (30 min) exhibits 10- to 15-fold higher affinity for cloned α1b-adrenergic receptors (pKi = 9.23) and cloned α1d-adrenergic receptors (pKi = 9.28) expressed in COS-7 cells than for cloned α1a-adrenergic receptors (pKi = 8.18), and fails to distinguish between the α1b and α1d subtypes[1].
Cyclazosin (2h) binds with high affinity to human α1A, α1B, and α1D adrenergic receptors expressed in CHO-K1 cells. It shows 9.5-fold selectivity for the α1D subtype over the α1A subtype, and exhibits biphasic binding characteristics at the α1D adrenergic receptor[5].
Cyclazosin (0.01-100 μM; 2 h, followed by overnight incubation) acts as a partial agonist of CXCR4 and ACKR3, inducing β-arrestin recruitment (with EC50 values of 16 μM and 10 μM, respectively); its CXCR4 activity is inhibited by AMD3100 (HY-10046), while its ACKR3 activity remains unaffected[2].
Cyclazosin (100 μM; 5-45 min) induces ERK1/2 phosphorylation in HEK293 cells overexpressing either ACKR3 or CXCR4. In ACKR3-expressing cells, its phosphorylation time course is consistent with that of CXCL12 and is not affected by AMD3100, whereas in CXCR4-expressing cells, it exhibits a delayed and persistent pattern, and this effect is inhibited by AMD3100[2].
Cyclazosin (200 μM) binds directly to CXCR4 and ACKR3 in membrane preparations, and induces detectable structural rearrangements in both receptors as detected by 1H-13C HSQC NMR[2].
Cyclazosin (100 μM; 15-30 min) induces time-dependent internalization of endogenous CXCR4 and ACKR3 in primary human aortic vascular smooth muscle cells, and their surface expression levels decrease to approximately 35% of the baseline level after 30 minutes of treatment with 100 μM Cyclazosin[2].
Cyclazosin (10-13-10-7 M; 3 h) potently inhibits CXCL12-induced chemotaxis of primary human aortic vascular smooth muscle cells, with an IC50 of 11.6 pM, and shows no cytotoxicity at concentrations up to 1 mM[2].
Cyclazosin (0.1-10 nM; 1 hour) acts as a high-affinity antagonist of α1B-adrenergic receptor-mediated adrenaline-induced contraction of human umbilical vein rings, with a pA2 value of 9.75[6].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Cell Line:HEK293 cells transfected with HA-CXCR4 and HA-ACKR3 plasmid
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Concentration:100 μM; 10 μM AMD3100 (pre-incubation)
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Incubation Time:0, 5, 15, 30 and 45 min; 20 min (after 15 min AMD3100 pre-incubation)
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Result:In CXCR4-overexpressing HEK293 cells, cyclazosin induced a 3-fold increase in ERK1/2 phosphorylation with a delayed and prolonged time course compared to CXCL12 (peak at 15–30 min vs 5 min), and this effect was significantly reduced by AMD3100.
In ACKR3-overexpressing cells, cyclazosin induced ERK1/2 phosphorylation with a time course identical to that of CXCL12, albeit with a weaker magnitude than CXCL12 or prazosin, and AMD3100 had no effect on this response.
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Cell Line:Primary human aortic vascular smooth muscle cells (hVSMCs)
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Concentration:10-13, 10-12, 10-11, 10-10, 10-9, 10-8 and 10-7 M
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Incubation Time:3 h
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Result:Did not induce chemotaxis on its own. Potently and fully inhibited CXCL12-induced chemotaxis in a dose-dependent manner with an IC₅₀ of 11.6 pM. No cytotoxicity was observed at concentrations up to 1 mM in parallel Trypan Blue exclusion assays.
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:Conscious male C57 wild-type mice (22-35 g) implanted with radiotelemetric devices in the abdominal cavity under ether anesthesia; allowed 14 days recovery before experiments[4]
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Dosage:1.0 mg/kg
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Administration:s.c.; single dose
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Result:Did not significantly alter resting core body temperature compared to vehicle-treated mice.
Converted MDMA's typical monophasic hyperthermic response to a biphasic response, with an initial significant decrease in core temperature reaching a minimum 40 minutes after MDMA administration, followed by a temperature rise to levels similar to MDMA-only treated mice.
Failed to significantly reduce the maximum hyperthermia induced by MDMA compared to vehicle-pretreated controls.
Chemical Information
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CAS No. 139953-73-4
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Masse moléculaire 437.49
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Formule C23H27N5O4
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SMILES
O=C(C1=CC=CO1)N2[C@]3([H])[C@](CCCC3)([H])N(C4=NC5=C(C=C(C(OC)=C5)OC)C(N)=N4)CC2
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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
Références
[1]. Giardinà D, et al. Receptor binding profile of cyclazosin, a new alpha 1B-adrenoceptor antagonist. Eur J Pharmacol. 1995 Dec 4;287(1):13-6. [Content Brief]
[2]. Gao X, et al. Partial agonist activity of α1-adrenergic receptor antagonists for chemokine (C-X-C motif) receptor 4 and atypical chemokine receptor 3. PLoS One. 2018 Sep 24;13(9):e0204041. [Content Brief]
[3]. Bexis S, et al. Role of alpha1-adrenoceptor subtypes in the effects of methylenedioxy methamphetamine (MDMA) on body temperature in the mouse. British journal of pharmacology. 2008 Feb;153(3):591-7. [Content Brief]
[4]. Alsufyani HA, et al. Both α- and α-adrenoceptor subtypes are involved in contractions of rat spleen. Pharmacological reports : PR. 2021 Feb;73(1):255-260. [Content Brief]
[5]. Proudman RGW, et al. The affinity and selectivity of α-adrenoceptor antagonists, antidepressants, and antipsychotics for the human α1A, α1B, and α1D-adrenoceptors. Pharmacology research & perspectives. 2020 Aug;8(4):e00602. [Content Brief]
[6]. Errasti AE, et al. Human umbilical vein vasoconstriction induced by epinephrine acting on alpha1B-adrenoceptor subtype. American journal of obstetrics and gynecology. 2003 Nov;189(5):1472-80. [Content Brief]
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
Cyclazosin Related Classifications
HY-184086 Related Classifications
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