α adrenergic receptor

In vitro activity: Prazosin only causes angiogenesis and a marked rise in VEGF concentration in endothelial cells when eNOS is present. All larger blood vessels' smooth muscle cells have α1-adrenergic receptors, which are bound by prazosin.[1] Prazosin (0.1 nM) does not considerably lessen the vasomotor effect of exogenous noradrenaline, but it does block the increases in perfusion pressure brought on by electrical stimulation of the perimesenteric nerves.[2]

Prazosin (0.05-0.20 mg/kg s.c.), a dopamine D2 receptor antagonist, increases the suppression of the conditioned avoidance response when prazosin (0.2 mg kg(-1) s.c.) is administered in rats.[4] In rats that are free to move, the administration of 1 mg/kg of prazosin s.c. consistently lowers rearing but only marginally decreases horizontal activity during the first 10-minute study period. In rats that are free to roam around, prazosin successfully inhibits the locomotor stimulation brought on by either dosage of MK-801.[5]

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The increase of wall shear stress in capillaries by oral administration of the alpha1-adrenergic receptor antagonist prazosin induces angiogenesis in skeletal muscles. Because endothelial nitric oxide synthase (eNOS) is upregulated in response to elevated wall shear stress, we investigated the relevance of eNOS for prazosin-induced angiogenesis in skeletal muscles. Prazosin and/or the NOS inhibitor Nomega-nitro-L-arginine methyl ester (L-NAME) were given to C57BL/6 wild-type mice and eNOS-knockout mice for 14 days. The capillary-to-fiber (C/F) ratio and capillary density (CD; no. of capillaries/mm2) were determined in frozen sections from extensor digitorum longus (EDL) muscles of these mice. Immunoblotting was performed to quantify eNOS expression in endothelial cells isolated from skeletal muscles, whereas VEGF (after precipitation with heparin-agarose) and neuronal NOS (nNOS) concentrations were determined in EDL solubilizates. In EDL muscles of C57BL/6 mice treated for 14 days, the C/F ratio was 28% higher after prazosin administration and 11% higher after prazosin and L-NAME feeding, whereas the CD increased by 21 and 13%, respectively. The C/F ratio was highest after day 4 of prazosin treatment and decreased gradually to almost constant values after day 8. Prazosin administration led to elevation of eNOS expression. VEGF levels were lowest at day 4, whereas nNOS values decreased after day 8. In EDL muscles of eNOS-knockout mice, no significant changes in C/F ratio, CD, or VEGF and nNOS expression were observed in response to prazosin administration. Our data suggest that the presence of eNOS is essential for prazosin-induced angiogenesis in skeletal muscle, albeit other signaling molecules might partially compensate for or contribute to this angiogenic activity. Furthermore, subsequent remodeling of the capillary system accompanied by sequential downregulation of VEGF and nNOS in skeletal muscle fibers characterizes shear stress-dependent angiogenesis. [1]

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Prazosin (0.5-2.0 mg/kg) blocked yohimbine-induced reinstatement of food and alcohol seeking, as well as footshock-induced reinstatement of alcohol seeking. Guanfacine attenuated yohimbine-induced reinstatement of alcohol seeking at the highest dose (0.5 mg/kg), but its effect on yohimbine-induced reinstatement of food seeking was not significant. Neither prazosin nor guanfacine affected high-rate food-reinforced responding. Conclusions: Results demonstrate an important role of postsynaptic alpha-1 adrenoceptors in stress-induced reinstatement of alcohol and food seeking[3].

Background: Prazosin, a non-selective α1-adrenoceptor and a selective α2B-adrenoceptor antagonist, is reported to possess anti-cancer activity in some types of cancer. The aim of this study was to investigate the effect of prazosin on acute myeloid leukemia (AML) and the underlying relevant mechanisms.
Methods: AML cell lines U937 and HL60 were treated with different concentration of prazosin (5, 10 and 15 μM), CCK8 and flow cytometry assays were performed to examine the effects of prazosin on cell viability, cell cycle distribution and apoptosis. Western blot assay was used to detect the expression of related proteins.
Results: We observed that prazosin inhibited cell viability of U937 and HL60 cells and induced the rate of apoptosis in a dose-dependent manner, as well as induced cell cycle arrest at G1 phase. The activation of PI3K/Akt/mTOR signaling pathway was significantly suppressed by prazosin via reducing the phosphorylation of Akt and mTOR. Moreover, by RNA-seq analysis, we found that the expression of tensin 1 (TNS1) was down-regulated by prazosin, and down-regulation of TNS1 could inhibit cell viability of U937 and HL60 cells, as well as induced cell apoptosis. The PI3K/Akt/mTOR signaling pathway was also suppressed by depletion of TNS1. Furthermore, up-regulation of TNS1 could reverse the effects of prazosin on viability and apoptosis in U937 and HL-60 cells, as well as the PI3K/Akt/mTOR signaling pathway.
Conclusion: These results highlight an anti-cancer activity of prazosin on AML by inhibiting the PI3K/Akt/mTOR pathway and targeting TNS1. [Biomed Pharmacother. 2020 Apr:124:109731]

In exp. 1, we trained rats to self-administer alcohol (12% w/v, 1 h/day), and after extinction of alcohol-reinforced lever pressing, we tested prazosin's (0.5, 1.0, and 2.0 mg/kg, i.p.) or guanfacine's (0.125, 0.25, and 0.5 mg/kg, i.p.) effect on yohimbine (1.25 mg/kg, i.p.)-induced reinstatement; we also examined prazosin's effect on intermittent-footshock-stress-induced reinstatement. In exp. 2, we trained food-restricted rats to self-administer 45 mg food pellets and first examined prazosin's or guanfacine's effects on food-reinforced responding, and then, after extinction of lever presses, on yohimbine-induced reinstatement. [3]

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Animals and experimental procedures. [1]
In accordance with approvals obtained from the university and state authorities for animal welfare, this study was performed on C57BL/6 wild-type mice and eNOS-knockout mice, which were bred in our animal care facility under standard conditions. The eNOS-knockout strain was originally purchased from Jackson Laboratories. For the experiments, 195 healthy mice weighing 25–30 g (3–5 mo old) were used. The mice were anesthetized with ketamine and killed by heart excision.
To dissolve prazosin, tap water was adjusted with HCl to pH 5.8 and heated to 60°C before addition of 50 mg/l ground prazosin powder. This concentration has been shown to induce angiogenesis in rats. The inhibitor Nω-nitro-l-arginine methyl ester (l-NAME), which is specific for all NOS forms, was obtained from Sigma and freshly prepared in a concentration of 1 mg/ml dissolved in tap water as previously described to be applied daily. Because a mouse drinks ∼3 ml of water/day, 150 μg of prazosin and/or 3 mg of l-NAME, respectively, were required each day.
For determination of angiogenesis and its relation to NO availability, mice from each of the two mouse strains were assigned to four groups consisting of at least five animals each. For 14 days, one group was treated with prazosin dissolved in drinking water, whereas the control group received water without prazosin. A third group of mice was treated with a combination of prazosin and l-NAME, and a forth group was fed with l-NAME alone.
The time course of prazosin-induced angiogenesis was investigated in groups of C57BL/6 mice and eNOS-knockout mice (3 animals/group) treated with prazosin for 3, 4, 8, or 14 days compared with control animals that received tap water alone (0 days).

Absorption, Distribution and Excretion
Peak plasma concentrations are reached approximately 3 hours after oral administration. Prazosin dosage is linearly related to steady-state plasma concentration. The drug is primarily excreted via bile and feces. The clearance rate is approximately 0.6 L/kg. Clearance is reduced in patients with congestive heart failure. Renal impairment has no significant effect on drug clearance. Metabolism/Metabolites Prazosin hydrochloride is actively metabolized in animals. This metabolism primarily occurs through hepatic demethylation and conjugation. Similar prazosin metabolism has been observed in some human or in vitro human cell studies. Biological Half-Life The plasma half-life is approximately 2–3 hours.

Hepatotoxicity
Prazosin is associated with a low incidence of elevated serum transaminase levels; in controlled trials, the rate of elevation was not higher than in the placebo group. These elevations are transient and do not require dose adjustment. No clinically significant acute liver injury caused by prazosin has been reported in the literature, but the sponsor has received reports of cholestatic hepatitis. Among alpha-adrenergic receptor antagonists, alfuzosin is the most commonly associated with liver injury, while other alpha-blockers have only a few isolated cases with insufficient evidence. Therefore, acute symptomatic liver injury caused by prazosin is very rare, and severe hepatotoxicity, even if it occurs, is extremely rare. Probability score: E (Unproven but suspected rare cause of clinically significant liver injury). Pregnancy and Lactation Effects ◉ Overview of Use During Lactation Due to limited information on the use of prazosin during lactation, other medications may be preferred, especially in breastfeeding newborns or preterm infants.
◉ Effects on breastfed infants
No published information found as of the revision date.
◉ Effects on lactation and breast milk
No published information found on lactating women as of the revision date. Prazosin does not affect serum prolactin concentrations in hypertensive patients. For mothers who have established lactation, prolactin levels may not affect their ability to breastfeed.

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Protein binding
Highly binds to proteins, with binding rates up to 97% to albumin and α1-acid glycoprotein. Prazosin is considered to bind primarily (approximately 80-90%) to albumin.

[1]. Am J Physiol Heart Circ Physiol. 2004 Nov;287(5):H2300-8.

[2]. J Pharmacol Exp Ther. 1997 Aug;282(2):691-8.

[3]. Psychopharmacology (Berl). 2011 Nov;218(1):89-99.

[4]. J Neural Transm (Vienna). 2000;107(10):1229-38.

[5]. Eur J Pharmacol. 1996 Aug 1;309(1):1-11.

[6]. J Chem Neuroanat. 1997 Jul;13(2):115-39.

[7]. Neurosci Lett. 2000 Mar 24;282(3):161-4.

Prazosin belongs to the piperazine class of compounds. Its structure consists of a piperazine molecule with furan-2-ylcarbonyl and 4-amino-6,7-dimethoxyquinazoline-2-yl groups substituted at positions 1 and 4, respectively. It is an antihypertensive drug, an alpha-adrenergic receptor antagonist, and an EC 3.4.21.26 (prolyl oligopeptidase) inhibitor. Prazosin belongs to the piperazine, quinazoline, furan, monocarboxylic acid amide, and aromatic ether classes of compounds. Prazosin is a drug used to treat hypertension. It is manufactured and marketed by Pfizer and was initially approved by the U.S. Food and Drug Administration (FDA) in 1988. It belongs to the alpha-1 receptor antagonist class of drugs. Recently, many studies have evaluated the benefits of this drug in controlling symptoms of post-traumatic stress disorder (PTSD) and related nightmares. Prazosin is an alpha-adrenergic blocker. The mechanism of action of prazosin is as an alpha-adrenergic receptor antagonist. Prazosin is a non-selective alpha-adrenergic receptor antagonist (alpha-blocker) used to treat hypertension. The incidence of transient elevations in serum transaminases caused by prazosin is low, and no clear association has been found with clinically significant acute liver injury. Prazosin is a synthetic piperazine derivative and an alpha-1 adrenergic receptor inhibitor, primarily used as an antihypertensive drug. Prazosin's effects are most pronounced in large resistance vessels (i.e., arterioles), reducing systemic vascular resistance (SVR) without causing rebound or reflex tachycardia. This drug can also reduce bladder sphincter tone to some extent, allowing the bladder opening to the urethra, thereby relieving urinary symptoms caused by benign prostatic hyperplasia. This product is a selective alpha-1 adrenergic receptor antagonist used to treat heart failure, hypertension, pheochromocytoma, Raynaud's disease, benign prostatic hyperplasia, and urinary retention. See also: Prazosin hydrochloride (salt form). Drug Indications This product is indicated for the treatment of hypertension. Prazosin can be used alone or in combination with other antihypertensive drugs, including diuretics or beta-adrenergic blockers. Prazosin does not negatively affect lung function and therefore can be used to treat hypertension in patients with asthma or chronic obstructive pulmonary disease (COPD). FDA Label Mechanism of Action Alpha-adrenergic receptors are essential for blood pressure regulation in the human body. Both α1 and α2 types of α receptors are involved in blood pressure regulation. α1 receptors are located postsynaptic (after the neural junction, i.e., the gap between the nerve fiber and the target tissue). In this case, the target tissue is vascular smooth muscle. Activation of these receptors raises blood pressure. Prazosin inhibits postsynaptic α1 adrenergic receptors. This inhibition blocks the vasoconstrictive effects of catecholamines (adrenaline and noradrenaline), resulting in peripheral vasodilation. Adrenaline and noradrenaline cause vasoconstriction by activating adrenergic receptors, typically raising blood pressure. Effects on Blood Pressure The pharmacodynamics and therapeutic effects of this drug include lowering blood pressure, as well as significantly reducing cardiac output, heart rate, renal blood flow, and glomerular filtration rate. The decrease in blood pressure may occur in both standing and supine positions. Many of these effects are due to vasodilation caused by prazosin, thereby reducing peripheral resistance. Peripheral resistance refers to the resistance a blood vessel exerts to the flow of blood through it. When blood vessels constrict (narrow), resistance increases; when blood vessels dilate (widen), peripheral resistance decreases, thus lowering blood pressure. Effects on Sleep Disorders Related to Post-Traumatic Stress Disorder (PTSD) Some studies have shown that this drug can improve sleep in patients with insomnia caused by nightmares and PTSD, which is resulting from a state of hyperarousal. This effect may be achieved by inhibiting adrenergic stimulation during hyperarousal.

C₁₉H₂₁N₅O₄

383.40

383.159

19216-56-9

Prazosin hydrochloride;19237-84-4;Prazosin-d8;1006717-55-0

4893

White to off-white solid powder

1.352g/cm3

638.4ºC at 760mmHg

278-280ºC

339.9ºC

3.4E-16mmHg at 25°C

1.651

1.717

1

8

4

28

544

0

IENZQIKPVFGBNW-UHFFFAOYSA-N

InChI=1S/C19H21N5O4/c1-26-15-10-12-13(11-16(15)27-2)21-19(22-17(12)20)24-7-5-23(6-8-24)18(25)14-4-3-9-28-14/h3-4,9-11H,5-8H2,1-2H3,(H2,20,21,22)

[4-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperazin-1-yl]-(furan-2-yl)methanone

prazosin; 19216-56-9; Furazosin; Prazosine; Prazosinum; Prazosina; Prazocin; Prazosine [INN-French];

2934.99.9001

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.

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

DMSO : ~41.67 mg/mL (~108.69 mM)
H2O : < 0.1 mg/mL

Solubility in Formulation 1: ≥ 5 mg/mL (13.04 mM) (saturation unknown) in 10% DMSO + 40% PEG300 +5% Tween-80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 50.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 + to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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