Debrisoquin sulfate primarily targets the adrenergic nervous system, acting as an adrenergic neuron-blocking agent. It does not act by inhibiting norepinephrine binding to its receptors but rather by interfering with the release and distribution of norepinephrine at sympathetic effector junctions. It is taken up by norepinephrine transporters and concentrated in neurotransmitter vesicles, gradually depleting norepinephrine stores. The compound also serves as a classic substrate for the polymorphic cytochrome P450 enzyme CYP2D6.

As an adrenergic blocker, debrisoquin sulfate inhibits the release of norepinephrine upon arrival of an action potential. Unlike ganglionic blockers, it equally inhibits both α- and β-adrenergic receptor-mediated responses. Its primary use in research is as a probe for CYP2D6 activity, as its metabolism is dependent on this enzyme. The compound has also been identified as a TMPRSS2 inhibitor, with an IC50 of 22 μM for inhibiting SARS-CoV-2 entry into human lung cells via a TMPRSS2-dependent manner.

In vivo, debrisoquin sulfate acts as an antihypertensive agent by lowering blood pressure. It produces a slight decrease in peripheral resistance and cardiac output due to sympathetic nerve blockade, lowering blood pressure in the supine position. It further reduces blood pressure by diminishing vasoconstriction caused by reflex sympathetic activity in the upright position, thereby reducing venous return and cardiac output. The compound has been used for the treatment of moderate to severe hypertension, either alone or as an adjunct therapy, and for renal hypertension.

A typical CYP2D6 phenotyping assay involves incubating debrisoquin with human liver microsomes or recombinant CYP2D6 in a reaction buffer containing NADPH. The reaction is initiated by adding the substrate and terminated by cooling and adding a stop solution. The formation of the primary metabolite, 4-hydroxydebrisoquin, is quantified using HPLC or LC-MS/MS. Metabolic activity is expressed as the rate of metabolite formation per milligram of protein. The assay is used to determine the enzyme kinetics (Km, Vmax) and to assess the inhibitory effects of test compounds on CYP2D6 activity.

Cellular assays for debrisoquin are not typical; however, the compound has been studied in the context of SARS-CoV-2 infection. In such an assay, human lung cell lines are treated with debrisoquin at various concentrations (e.g., 0.1-100 μM) prior to or concurrent with exposure to SARS-CoV-2 pseudovirus. After incubation, the percentage of infected cells is determined by measuring reporter gene expression (e.g., luciferase activity). The IC50 value for inhibiting viral entry is calculated from the dose-response curve. Cell viability is monitored to ensure that the observed antiviral effects are not due to cytotoxicity.

To evaluate the antihypertensive effect of debrisoquin, spontaneously hypertensive rats (SHR) or normotensive rats are used. Animals are instrumented with telemetry devices or tail-cuff systems to measure blood pressure. Debrisoquin sulfate is administered orally or intraperitoneally at doses ranging from 1 to 10 mg/kg. Blood pressure and heart rate are monitored over 24 hours post-administration. The antihypertensive efficacy is expressed as the maximum decrease in mean arterial pressure (MAP) and the duration of action. The compound's effects on sympathetic nerve activity can also be assessed by measuring plasma norepinephrine levels.

Metabolism / Metabolites
Liver.
Known metabolites of debuisoquinoline include 4-hydroxydebuisoquinoline.

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Debrisoquin is extensively metabolized in the liver, primarily by CYP2D6 to 4-hydroxydebrisoquin. This metabolism exhibits genetic polymorphism, with individuals carrying certain isoenzymes unable to properly metabolize debrisoquin. The compound's pharmacokinetic profile is characterized by this polymorphic metabolism, which is the basis for its use as a probe drug for phenotyping CYP2D6 activity. It is an adrenergic neuron blocker with effects similar to guanethidine.

The toxicity of debrisoquin is related to its pharmacological action as an adrenergic neuron blocker. Adverse effects may include orthostatic hypotension and other cardiovascular effects associated with sympathetic blockade. As a drug that was previously used clinically for hypertension, its safety profile has been established. At research-grade purity (≥98%), it is intended for laboratory use only and not for human administration. Standard safety precautions should be observed when handling this compound.

Clin Pharmacol Ther. 2001 Oct;70(4):327-35.

Debrisoquin belongs to the isoquinoline and carboxymidine classes of compounds. It has various effects, including antihypertensive activity, adrenergic agonist, sympathetic nerve blocker, and human metabolite production. It is an adrenergic neuron blocker, with effects similar to guanethidine. Notably, it is also a substrate of the polymorphic cytochrome P-450 enzyme. Individuals carrying certain isoenzymes of this enzyme cannot properly metabolize Debrisoquin, as well as many other clinically significant drugs. They are generally referred to as having Debrisoquin 4-hydroxylase polymorphism. There are reports of Debrisoquin metabolism in Homo sapiens and Euglena. It is an adrenergic neuron blocker, with effects similar to guanethidine. Notably, it is also a substrate of the polymorphic cytochrome P-450 enzyme. Individuals carrying certain specific isoenzymes of this enzyme cannot properly metabolize this drug, as well as many other clinically significant drugs. They are generally referred to as having norepinephrine 4-hydroxylase polymorphism. Drug Indications For the treatment of moderate to severe hypertension, either alone or as an adjunct therapy, and for the treatment of renal hypertension. Mechanism of Action Norepinephrine does not act on effector cells by inhibiting the binding of norepinephrine to its receptors, but rather by inhibiting or interfering with the release and/or distribution of norepinephrine at sympathetic effector junctions. It is taken up by norepinephrine transporters and concentrated in norepinephrine neurotransmitter vesicles, replacing the norepinephrine in these vesicles. This leads to the gradual depletion of norepinephrine stores in nerve endings. Once inside the nerve ending, it blocks the release of norepinephrine upon the arrival of an action potential. Unlike ganglion blockers, debuquine inhibits α- and β-adrenergic receptor-mediated responses to an equal degree, but does not produce parasympathetic blockade. Because sympathetic nerve blockade leads to a slight decrease in peripheral resistance and cardiac output, debuquine lowers blood pressure in the supine position. It further lowers blood pressure by reducing the degree of vasoconstriction caused by reflex sympathetic activity in the upright position, thereby further reducing venous return and cardiac output.

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Pharmacodynamics
Debuquine is an adrenergic neuron blocker with effects similar to guanethidine. It is a substrate of the polymorphic cytochrome P-450 enzyme. Individuals carrying certain isoenzymes of this enzyme cannot properly metabolize debuquine, as well as many other clinically significant drugs. They are often referred to as having debuquine 4-hydroxylase polymorphism.

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Debrisoquin sulfate is classified as an isoquinoline and carboxymidine compound. It has various biological effects, including antihypertensive activity, adrenergic agonism, and sympathetic nerve blockade. It is also a substrate of the polymorphic cytochrome P-450 enzyme, and individuals with certain isoenzymes are referred to as having debrisoquin 4-hydroxylase polymorphism. The compound's metabolism has been reported in Homo sapiens and Euglena. It is available as a research chemical under catalog number V5001.

C20H26N6O4S

446.523242473602

448.189

581-88-4

Debrisoquin;1131-64-2

2966

Light yellow to yellow solid powder

309.8ºC at 760 mmHg

278-280°, 284-285° or 266-268° (H2O)

141.1ºC

3.78

2

1

1

13

202

0

CAYGYVYWRIHZCQ-UHFFFAOYSA-N

InChI=1S/2C10H13N3.H2O4S/c2*11-10(12)13-6-5-8-3-1-2-4-9(8)7-13;1-5(2,3)4/h2*1-4H,5-7H2,(H3,11,12);(H2,1,2,3,4)

3,4-dihydro-1H-isoquinoline-2-carboximidamide; sulfate (2:1)

Isocaramidine sulfate; Ro 5-3307; Debrisoquine; Ro-53307; Debrisoquina; Debrisoquin; Ro5-3307; Debrisochinum; Tendor; Debrisoquin sulfate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

H2O : ~10.42 mg/mL (~46.46 mM)

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.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*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).

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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)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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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).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)