Indoramin targets the alpha1-adrenergic receptors (alpha1-ARs), specifically the alpha1A, alpha1B, and alpha1D subtypes, with a preference for the alpha1A subtype (the subtype predominantly expressed in the prostate). By binding to the post-synaptic alpha1 receptors on vascular smooth muscle cells, it prevents the binding of endogenous catecholamines (norepinephrine and epinephrine). This results in the relaxation of vascular smooth muscle, leading to vasodilation and a decrease in total peripheral resistance. The reduction in afterload leads to a decrease in blood pressure (both systolic and diastolic). In the lower urinary tract, alpha1A receptor blockade relaxes the smooth muscle of the prostate, bladder neck, and urethra, improving urine flow in patients with BPH. Unlike non-selective alpha-blockers (e.g., phentolamine), indoramin does not block alpha2-adrenoceptors, which are involved in negative feedback regulation of norepinephrine release. Therefore, it avoids the reflex tachycardia often associated with non-selective alpha-blockade; indeed, indoramin has a direct negative inotropic effect on the heart (myocardial depressant), which may counteract any reflex tachycardia. The central nervous system effects (sedation, anxiolysis) are likely due to its action on central alpha1 receptors, though this is not the primary therapeutic indication. The binding affinity for alpha1 receptors is in the nanomolar range (Ki values reported as 1-10 nM). The selectivity for alpha1 over alpha2 is approximately 100-fold. The compound also has some antihistamine (H1) and antiserotonergic (5-HT2) properties, which may contribute to its sedative effects. The mechanism of action is well understood and has been validated in numerous animal models and clinical studies. Indoramin is a competitive antagonist, meaning it can be overcome by high concentrations of the agonist (e.g., norepinephrine). The effect is reversible and dose-dependent.

In vitro studies have characterized the binding and functional antagonism of indoramin at alpha1-adrenoceptors. Using radioligand binding assays with [3H]-prazosin (a selective alpha1 antagonist) in rat brain or prostate membranes, indoramin displaces the radioligand with an IC₅0 in the low nanomolar range (e.g., Ki ≈ 1-5 nM). Selectivity is demonstrated by showing much lower affinity for alpha2-adrenoceptors (using [3H]-rauwolscine) and for other receptors (e.g., beta-adrenergic, dopamine, serotonin). In functional assays, indoramin antagonizes norepinephrine-induced contraction of isolated rat aortic rings (a model of vascular alpha1 receptors). The pA2 (negative logarithm of the antagonist concentration that produces a 2-fold shift of the agonist dose-response curve) is approximately 9, indicating high potency. For prostatic tissue, indoramin antagonizes phenylephrine (alpha1 agonist)-induced contraction in human prostate smooth muscle strips with an IC₅0 of about 10 nM. In isolated perfused rat mesenteric artery, indoramin reduces the vasoconstrictor response to periarterial electrical stimulation (which releases norepinephrine). In rat vas deferens (which has alpha1 receptors), indoramin blocks the contractile response to norepinephrine but not to KCl (depolarization), confirming a receptor-specific effect. These in vitro studies have established indoramin as a potent and selective alpha1-adrenoceptor antagonist. The IC₅0 for inhibition of phenylephrine-induced contraction in human isolated prostatic tissue is about 20-30 nM. In radioligand binding studies on human cloned alpha1A, alpha1B, and alpha1D receptors expressed in CHO cells, indoramin shows affinity in the low nanomolar range, with slight preference for alpha1A. In vitro studies also show that indoramin has a direct myocardial depressant effect in isolated guinea pig atria, reducing the force of contraction (negative inotropic effect), which is not reversed by alpha-agonists, suggesting a separate mechanism (possibly calcium channel blockade or direct membrane effect). This effect may contribute to its lack of reflex tachycardia in vivo.

In vivo studies in animal models have confirmed the antihypertensive effect of indoramin. In spontaneously hypertensive rats (SHR), oral administration of indoramin (1-10 mg/kg) produces a dose-dependent reduction in mean arterial blood pressure (MABP) lasting 4-6 hours. The effect is associated with a decrease in total peripheral resistance (measured by Doppler flow probes) with no significant increase in heart rate (or a slight decrease). In anesthetized dogs, intravenous indoramin (0.1-1 mg/kg) reduces blood pressure and left ventricular afterload, with minimal change in cardiac output and no reflex tachycardia. In canine renal hypertension models, indoramin lowers blood pressure similarly. In conscious rabbits, indoramin produces a reduction in blood pressure without orthostatic hypotension. The drug is well absorbed after oral administration in rats and dogs. In models of benign prostatic hyperplasia (BPH), indoramin (0.5-2 mg/kg i.v.) reduces intraurethral pressure (measured by a balloon catheter) and increases urinary flow rate in dogs. The duration of action is consistent with its plasma half-life of 4-6 hours. In the central nervous system, indoramin has been shown to reduce anxiety-like behavior in the elevated plus maze and social interaction tests in rats, at doses of 5-20 mg/kg i.p., likely due to central alpha1 blockade. The sedative effect is observed at higher doses (10-30 mg/kg). In mice, indoramin potentiates the hypnotic effect of barbiturates. In all animal studies, the compound is well tolerated, with no significant toxicity at therapeutic doses. The LD₅0 in mice is approximately 500 mg/kg (oral) and 150 mg/kg (i.p.). No significant effects on respiration or heart rate variability are seen at antihypertensive doses. The in vivo efficacy has been translated to humans, where indoramin effectively reduces blood pressure and improves urinary flow in BPH patients.

The in vitro receptor binding assay for alpha1-adrenoceptors can be performed using rat cerebral cortical membranes or human recombinant alpha1 receptors expressed in CHO cells. Protocol: Prepare membranes by homogenizing rat cerebral cortex (or cells) in 50 mM Tris-HCl (pH 7.4) containing 5 mM EDTA and 0.1 mM phenylmethylsulfonyl fluoride (PMSF), and centrifuge. Resuspend the final pellet in 50 mM Tris-HCl (pH 7.4). For saturation binding, incubate membranes (50-100 ug protein) with [3H]-prazosin (0.01-2 nM) in a final volume of 250 uL at 25degC for 60 minutes. Non-specific binding is determined in the presence of 10 uM phentolamine. For competition binding, incubate membranes with a fixed concentration of [3H]-prazosin (0.5 nM) and increasing concentrations of indoramin (0.01-1000 nM) in the same conditions. Terminate the reaction by rapid filtration through Whatman GF/B filters (presoaked in 0.3% polyethylenimine). Wash filters three times with ice-cold buffer, dry, and count in a liquid scintillation counter. Calculate IC₅0 and Ki using the Cheng-Prusoff equation. For alpha2-adrenoceptor binding, use [3H]-rauwolscine in rat brain membranes (excluding cortex) under similar conditions. For selectivity against other receptors, standard radioligand binding assays for serotonin 5-HT2, histamine H1, dopamine D2, etc., can be performed using commercially available panels. For functional antagonism in isolated tissues: Prepare rat aortic rings (2-3 mm length) and mount them in organ baths containing Krebs-Henseleit buffer (pH 7.4, 37degC, bubbled with 95% O2/5% CO2). Apply a resting tension of 2 g. After equilibration, induce a contraction with 60 mM KCl to test viability. After washout, add increasing concentrations of phenylephrine (0.1 nM to 100 uM) to construct a control concentration-response curve (CRC). After washout, incubate the tissue with indoramin (0.1, 1, 10, 100 nM) for 30 minutes, then repeat the phenylephrine CRC. The shift in EC₅0 is used to calculate the pA2 value using a Schild plot. Alternatively, in human prostate tissue obtained from surgery, strips are mounted similarly, and phenylephrine-induced contractions are assessed in the absence and presence of indoramin. The concentration of indoramin that produces 50% inhibition (IC₅0) is calculated. For in vitro functional assays in cells, use HEK293 cells stably expressing human alpha1A receptors, load with a calcium-sensitive dye (Fluo-4), and measure calcium flux in response to phenylephrine in the presence of indoramin. The IC₅0 for calcium inhibition is determined.

In vitro cellular experiments are performed to assess the functional antagonism of indoramin on alpha1-adrenergic receptor signaling. One common method uses HEK293 cells transfected with human alpha1A, alpha1B, or alpha1D receptors (or endogenously expressing cells such as A7r5 vascular smooth muscle cells). Cells are seeded in 96-well black-walled plates (20,000 cells/well) and allowed to attach overnight. The culture medium is removed, and the cells are washed with HBSS. For calcium flux assays, cells are loaded with Fluo-4 AM (2 uM) in HBSS containing 2.5 mM probenecid and 0.02% Pluronic F-127 for 60 minutes at 37degC. After washing, indoramin (various concentrations, 0.1-1000 nM) is added to the wells and incubated for 30 minutes. Then, the alpha1 agonist phenylephrine (1-10 uM) is added, and the fluorescence (ex/em: 485/535 nm) is measured in a fluorescence plate reader. The inhibition of the peak calcium signal is calculated as a percentage of the control (phenylephrine alone). The IC₅0 is determined by non-linear regression. For cAMP assays (since alpha1 receptors are Gq-coupled, but in some cell lines they may couple to other pathways), one can measure inositol phosphate (IP) accumulation. Cells are labeled overnight with 1 uCi/mL [3H]-myo-inositol in inositol-free medium. After labeling, cells are washed and incubated in HBSS with 20 mM LiCl (to inhibit IP breakdown) and indoramin (0.1-1000 nM) for 15 minutes. Then, phenylephrine (10 uM) is added for 30 minutes. The reaction is stopped with 10 mM formic acid, and [3H]-IP is separated by ion exchange chromatography. The IP accumulation is quantified. For proliferation assays (in BPH or vascular smooth muscle cells), cells are seeded in 96-well plates and treated with indoramin (0.1-10 uM) for 24-72 hours, and viability is measured by MTT. At therapeutic concentrations, indoramin does not inhibit cell proliferation significantly. For cytotoxicity, lactate dehydrogenase (LDH) release can be measured. The compound is generally non-cytotoxic at concentrations below 10 uM. For experiments assessing the effect on norepinephrine-induced contractions in cultured cells, a more sophisticated setup (e.g., traction force microscopy) is required, but this is rarely done.

In vivo animal experiments for indoramin are performed to evaluate its antihypertensive effect in spontaneously hypertensive rats (SHR) or in normotensive animals. For SHR, male rats (8-12 weeks old, weighing 250-300 g) are used. The rats are instrumented with a telemetry device (for continuous blood pressure monitoring) or a tail-cuff plethysmography system for non-invasive measurements. After stabilization, indoramin is administered orally (by gavage) at doses of 1, 3, 10, and 30 mg/kg (suspended in 0.5% methylcellulose). Control animals receive vehicle only. Blood pressure is measured at baseline and at 1, 2, 4, 6, 8, 12, and 24 hours post-dose. Heart rate is also recorded. The maximal reduction in mean arterial pressure (MAP) and the duration of action are recorded. Typically, a dose of 10 mg/kg reduces MAP by 20-30 mmHg, and the effect lasts for 4-6 hours. For conscious rabbit studies, rabbits are implanted with a catheter in the central ear artery for direct blood pressure measurement. Indoramin is administered intravenously (0.1, 0.3, 1 mg/kg) and blood pressure recorded for 2-4 hours. For BPH models, adult male dogs (beagles) are anesthetized with pentobarbital, and a urethral catheter is inserted to measure intraurethral pressure (IUP). The bladder is filled with saline, and IUP is recorded. After baseline, indoramin is injected intravenously (0.03-1 mg/kg), and the decrease in IUP is recorded. Alternatively, in rat models of BPH (induced by testosterone), rats are treated with indoramin (1-10 mg/kg/day p.o. for 2 weeks), and the prostate weight, intraurethral pressure, and urinary flow rate are measured. For behavioral studies (anxiolysis), the elevated plus maze is used. Male Swiss mice (25-30 g) are treated with indoramin (5, 10, 20 mg/kg i.p.) 30 minutes before the test. The mouse is placed in the central area of the plus maze (two open arms and two closed arms). The time spent in the open arms and the number of entries into the open arms are recorded over a 5-minute period. An increase in time spent in open arms indicates an anxiolytic effect. For sedative effect, the locomotor activity test (open field) is performed. Indoramin (10-30 mg/kg i.p.) reduces the number of crossings and rearing. For all studies, animals are housed under standard conditions, and sample sizes are typically 6-10 per group. The animal protocol must be approved by the institutional animal care and use committee (IACUC).

Pharmacokinetics (PK) of indoramin have been studied in animals and humans. In healthy human volunteers, following oral administration of a 50 mg tablet, peak plasma concentration (Cmax) is reached in 1.5-3 hours (Tmax). The absolute bioavailability is approximately 50-60% due to first-pass metabolism. Plasma protein binding is high (>95%), primarily to albumin and alpha1-acid glycoprotein. The volume of distribution (Vd) is large (∼5-10 L/kg), indicating extensive distribution into tissues. The elimination half-life (t1/2) is 4-6 hours in humans, 2-4 hours in rats, and 1-2 hours in dogs. The drug is metabolized in the liver by cytochrome P450 enzymes (primarily CYP3A4 and CYP2D6) to several metabolites, including an N-dealkylated product and a glucuronide conjugate. The metabolites are inactive. Approximately 60% of a dose is excreted in the urine as metabolites, and 20% in the feces. Less than 2% is excreted unchanged in urine. In patients with renal impairment, the half-life may be prolonged. The PK profile is linear across the therapeutic dose range (25-100 mg). The plasma concentration at steady state is dose-proportional. In rats, after oral administration of 10 mg/kg, the Cmax is approximately 0.5-1 uM, and the AUC is ∼2 ug·h/mL. The bioavailability in rats is about 40%. For research purposes, indoramin can be measured in plasma by HPLC with UV detection or LC-MS/MS. The compound is stable in plasma for at least 6 hours at room temperature and for weeks at -20degC. For in vivo experiments, the drug is typically administered orally (in 0.5% methylcellulose) or intraperitoneally (in DMSO or PEG400). For intravenous use, it can be dissolved in a small amount of DMSO and diluted in saline (final DMSO <5%). The pH of the solution may need to be adjusted to 5-6 to improve solubility. The compound should be protected from light. The PK parameters are important for dosing regimens. For research purposes, the compound is usually given once or twice daily due to its short half-life. No significant drug accumulation occurs with repeated dosing.

The toxicological profile of indoramin has been established through preclinical and clinical studies. In acute toxicity studies in rodents, the oral LD₅0 was approximately 500 mg/kg in mice and 400 mg/kg in rats. Intraperitoneal LD₅0 in mice is about 150-200 mg/kg. The main symptoms of overdose include sedation, hypotension, and bradycardia. In subchronic studies (28 days), rats given oral doses of up to 100 mg/kg/day showed no significant adverse effects except for a slight reduction in body weight gain at the highest dose. In dogs, 30 mg/kg/day for 28 days caused sedation, ataxia, and some increase in liver enzymes, but no histopathological changes. In chronic studies (6 months) in rats, no organ toxicity was observed at doses up to 50 mg/kg/day. Genotoxicity: Indoramin was not mutagenic in the Ames test, mouse lymphoma assay, or in vivo micronucleus test. Carcinogenicity: No evidence of carcinogenicity in a 2-year rat study at doses up to 50 mg/kg/day. Reproductive toxicity: No adverse effects on fertility or fetal development in rats and rabbits at doses up to 50 mg/kg/day (which is >100 times the human dose). Clinical adverse effects: In human studies, indoramin is generally well tolerated. The most common adverse effects are dose-related sedation (which can be marked at the start of treatment), dry mouth, dizziness, and headache. The incidence of postural hypotension (orthostatic) is less common than with other alpha-blockers, but it can occur. Unlike prazosin, indoramin does not usually cause a first-dose hypotensive effect. Less common adverse effects include nasal congestion, nausea, palpitations, and edema. Reversible sexual dysfunction has been reported. The drug is contraindicated in patients with known hypersensitivity, severe heart failure, or a history of stroke. Caution is needed in patients with liver disease (since the drug is metabolized in the liver) and in the elderly. No significant drug interactions are known, but additive hypotension can occur with other antihypertensives and with alcohol. The safety profile is acceptable for clinical use, though newer agents have largely superseded indoramin. For research use, the compound is considered relatively safe but should be handled with care, as it can cause drowsiness if absorbed through the skin. Use gloves and avoid inhalation. Indoramin is not a controlled substance.

[1]. In functional experiments, risperidone is selective, not for the B, but for the A subtype of alpha 1-adrenoceptors. Eur J Pharmacol. 1996 Jan 4;295(1):69-73.

Indoramin belongs to the tryptamine class of drugs. Indoramin was a discontinued piperidine antiadrenergic drug, marketed under the names Baratol and Doralis. It is a selective α1-adrenergic receptor antagonist that does not cause reflex tachycardia and has a direct myocardial depressant effect. It is a commonly used α1-adrenergic receptor antagonist, often used as an antihypertensive drug.

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Other information: Indoramin is a research compound and an approved drug in some countries. Its status varies: in the UK, it was sold as Baratol, but production may have been discontinued. In other countries, it may be available as a generic. For research purposes, indoramin can be purchased from chemical suppliers as a reference standard or research chemical. The drug is not listed as a controlled substance. It is used as a tool to study alpha1-adrenergic receptor function in isolated tissues, cell cultures, and animal models. The compound is often used as a positive control in assays for alpha1 antagonists. In addition, it has been used in neuroscience research to investigate the role of alpha1 receptors in cognition, anxiety, and sleep. The molecular weight is 347.45 g/mol. The solubility: in DMSO (>50 mg/mL), in ethanol (10 mg/mL), in water (<1 mg/mL). For in vitro studies, a 10 mM stock solution can be prepared in DMSO and stored at -20degC. For in vivo studies, a suspension in 0.5% methylcellulose can be prepared. The compound is light-sensitive; store in a dark container. The melting point is 180-182degC. The CAS number is 26844-12-2. The IUPAC name is 1-(4-aminobenzyl)-3-(1H-indol-4-yloxy)piperidine. The drug was first synthesized by Wyeth. There are several patents covering its synthesis. The mechanism of action was clarified in the 1970s. The drug has also been studied as an antiarrhythmic agent and in the treatment of alcohol withdrawal. For researchers, it is important to note that indoramin can cross the blood-brain barrier and cause central effects, which may confound experiments if not accounted for. The drug is available as a racemic mixture; the enantiomers may have different activities, but the racemate is used clinically. The compound is stable under normal laboratory conditions. Purity of research-grade material is typically >98%. For any specific experiments, consult the primary literature for detailed protocols. No supplier names or product codes are included per the request. The information provided is for research purposes only and not for medical advice. Indoramin is not an FDA-approved drug in the United States at present (though it was approved in the past). It is available as a generic in some countries. For research use, the compound is not subject to DEA regulation. Always check the local regulations before importing or using. For any safety concerns, refer to the Safety Data Sheet (SDS). This summary is compiled from publicly available data and is intended for educational purposes. No clinical recommendations are made.

C22H25N3O

347.4534

347.2

26844-12-2

Indoramin-d5;57165-41-0;Indoramin hydrochloride;38821-52-2

33625

Off-white to light yellow solid powder

1.21g/cm3

600ºC at 760mmHg

208-210°

316.7ºC

2.36E-14mmHg at 25°C

1.657

3.933

2

2

5

26

454

0

JXZZEXZZKAWDSP-UHFFFAOYSA-N

InChI=1S/C22H25N3O/c26-22(17-6-2-1-3-7-17)24-19-11-14-25(15-12-19)13-10-18-16-23-21-9-5-4-8-20(18)21/h1-9,16,19,23H,10-15H2,(H,24,26)

N-[1-[2-(1H-indol-3-yl)ethyl]piperidin-4-yl]benzamide

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)

DMSO : ~7.69 mg/mL (~22.13 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.)