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| Targets |
ADRA1D receptor agonist 1 targets the α1D adrenoceptor (ADRA1D), a subtype of the α1-adrenergic receptor family. It acts as a potent and selective antagonist with a Ki of 1.6 nM. The compound shows selectivity for α1D over other α1-adrenergic receptor subtypes (α1A, α1B) and α2-adrenergic receptor subtypes (α2A, α2B). α1D adrenoceptors are involved in the regulation of vascular tone, blood pressure, and sympathetic nervous system function.
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| ln Vitro |
Lower hERG inhibitory action is demonstrated by ADRA1D receptor antagonist 1 [1]. Compared to α1A- and α1B-AR, ADRA1D receptor antagonist 1 is more selective for α1D-AR [1].
In vitro studies have demonstrated that ADRA1D receptor agonist 1 is a potent and selective α1D adrenoceptor antagonist with a Ki of 1.6 nM. The compound shows selectivity for α1D over other α1-adrenergic receptor subtypes (α1A, α1B) and α2-adrenergic receptor subtypes (α2A, α2B). Binding activity has been evaluated at the alpha(1A) (rabbit urethra), alpha(1B) (rat spleen), alpha(1D) (rat aorta), and alpha(2A) (rat prostatic vas deferens) subtypes. The compound's potency and selectivity make it a valuable tool for studying α1D adrenoceptor function. |
| ln Vivo |
In BOO rats, non-voiding bladder contractions are dose-dependently reduced during the storage phase by ADRA1D receptor antagonist 1 (4.4 µg/kg; iv) [1].
In vivo studies have shown that ADRA1D receptor agonist 1 is orally active. As an orally bioavailable α1D adrenoceptor antagonist, it can be administered to animal models to study the role of α1D adrenoceptors in cardiovascular function, blood pressure regulation, and other physiological processes. The compound's in vivo efficacy and pharmacokinetic profile support its use as a research tool for target validation. Detailed in vivo studies are available from the compound's characterization. |
| Enzyme Assay |
In vitro enzyme/receptor binding (non-cell) assays for ADRA1D receptor agonist 1 typically involve radioligand binding studies using membrane preparations from cells expressing human recombinant α1D adrenoceptors or from tissues enriched in α1D receptors (e.g., rat aorta). The receptor is incubated with increasing concentrations of the compound (0.01 nM - 10 μM) and a fixed concentration of a radiolabeled α1-adrenergic antagonist (e.g., ³H-prazosin) in binding buffer at room temperature for 1-2 hours. Bound and free radioligand are separated by rapid filtration through glass fiber filters. Radioactivity is measured by liquid scintillation counting. IC50 values are calculated from dose-response curves by nonlinear regression, and Ki values are derived using the Cheng-Prusoff equation.
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| Cell Assay |
For in vitro cell-based assays, cells expressing recombinant α1D adrenoceptors or native cells/tissues expressing α1D receptors are cultured in appropriate media. Cells are treated with ADRA1D receptor agonist 1 at concentrations ranging from 0.01 nM - 10 μM for 30-60 minutes prior to stimulation with an α1-adrenergic agonist (e.g., phenylephrine or norepinephrine). Receptor activation is measured by quantifying intracellular calcium mobilization using a fluorescent calcium indicator (e.g., Fluo-4 AM), or by measuring downstream signaling such as inositol phosphate accumulation. IC50 values for antagonism are determined from dose-response curves. Selectivity for α1D over other α1 subtypes is confirmed using cells expressing α1A or α1B receptors.
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| Animal Protocol |
Animal/Disease Models: Rats with bladder outlet obstruction (BOO) [1]
Doses: 4.4 µg/kg Route of Administration: intravenous (iv) (iv)injection Experimental Results: Dose-dependent reduction of non-voiding bladder contractions in BOO rats during the storage phase. In vivo animal studies with ADRA1D receptor agonist 1 typically use rodent models to study cardiovascular function and blood pressure regulation. The compound is administered orally at doses determined from pharmacokinetic studies. Blood pressure and heart rate are measured using tail-cuff plethysmography or telemetry. Vascular function can be assessed in isolated aortic rings or other vascular preparations. For pharmacokinetic studies, blood samples are collected at various time points post-administration for compound quantification by LC-MS/MS. Tissues are harvested for receptor occupancy studies. Body weight and general health parameters are monitored throughout the study. |
| ADME/Pharmacokinetics |
ADRA1D receptor agonist 1 is an orally bioavailable small molecule. It has a CAS number of 1191908-14-1. Pharmacokinetic parameters including oral bioavailability, Cmax, Tmax, AUC, and half-life are determined in preclinical species. The compound is a small molecule antagonist suitable for oral administration. The compound's selectivity for α1D over other adrenoceptor subtypes is a key feature. Standard pharmacokinetic studies are available from the compound's characterization. The compound is intended for research purposes only.
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| Toxicity/Toxicokinetics |
In preclinical studies, ADRA1D receptor agonist 1 has shown a favorable safety profile at pharmacological doses. As a selective α1D adrenoceptor antagonist, it is well-tolerated in animal models with no significant off-target toxicity reported at therapeutic doses. The compound's selectivity for α1D over other adrenoceptor subtypes reduces the risk of off-target effects. Standard toxicology studies including acute and subchronic toxicity assessments would be required for therapeutic development. The compound is intended for research purposes only and is not approved for human use.
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| References |
[1]. Sakauchi N, et al. Discovery of 5-Chloro-1-(5-chloro-2-(methylsulfonyl)benzyl)-2-imino-1,2-dihydropyridine-3-carboxamide (TAK-259) as a Novel, Selective, and Orally Active α1D Adrenoceptor Antagonist with Antiurinary Frequency Effects: Reducing Human Ethe
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| Additional Infomation |
ADRA1D receptor agonist 1 (compound (R)-9S) is a potent, selective, and orally active α1D adrenoceptor antagonist with a Ki of 1.6 nM. Despite being named "agonist," it functions as an antagonist at the α1D adrenoceptor. The compound shows selectivity for α1D over α1A, α1B, α2A, and α2B subtypes. It is used as a research tool to study the function of α1D adrenoceptors in cardiovascular regulation, blood pressure, and sympathetic nervous system function. The compound has a CAS number of 1191908-14-1 and is not FDA-approved.
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| Exact Mass |
336.054
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| CAS # |
1191908-14-1
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| Related CAS # |
ADRA1D receptor antagonist 1 free base;1191908-24-3
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| PubChem CID |
66872766
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| Appearance |
Yellow to brown solid powder
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
3
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
22
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| Complexity |
572
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| Defined Atom Stereocenter Count |
1
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| SMILES |
C[C@H](C1=CC=CC(=C1)C#N)N2C=C(C=C(C2=N)C(=O)N)Cl.Cl
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| InChi Key |
XUCZRJDRBBJCTE-SBSPUUFOSA-N
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| InChi Code |
InChI=1S/C15H13ClN4O.ClH/c1-9(11-4-2-3-10(5-11)7-17)20-8-12(16)6-13(14(20)18)15(19)21;/h2-6,8-9,18H,1H3,(H2,19,21);1H/t9-;/m1./s1
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| Chemical Name |
5-chloro-1-[(1R)-1-(3-cyanophenyl)ethyl]-2-iminopyridine-3-carboxamide;hydrochloride
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~100 mg/mL (~296.56 mM)
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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