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
After administration of an oral dose, peak plasma concentrations are attained at approximately 3 hours. There is a linear association between the prazosin dose given and plasma concentration at steady state.
This drug is mainly excreted in the bile and the feces.
About 0.6 L/kg.
In patients with congestive heart failure, the clearance of this drug is decreased. Impairment of renal function does not have relevant effects on elimination.

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Metabolism / Metabolites
In animals, prazosin hydrochloride is heavily metabolized. This occurs through liver demethylation and conjugation. Some studies in humans or human cells in vitro show similar prazosin metabolism.

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Biological Half-Life
The plasma half-life is about 2-3 hours.

Hepatotoxicity
Prazosin has been associated with a low rate of serum aminotransferase elevations that in controlled trials was no higher than with placebo therapy. These elevations were transient and did not require dose modification. No instances of clinically apparent acute liver injury due to prazosin have been published in the literature, but reports of cholestatic hepatitis have been received by the sponsor. Among the alpha adrenergic receptor antagonists, the most frequently implicated agent in causing liver injury has been alfuzosin with only single, and not well documented cases linked to other alpha blockers. Thus, acute symptomatic liver injury due to prazosin is quite rare, and severe hepatotoxicity must be exceeding rare, if it occurs at all.
Likelihood score: E* (unproven but suspected rare cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Because little is available on the use of prazosin during breastfeeding, an alternate drug may be preferred, especially while nursing a newborn or preterm infant.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information in nursing mothers was not found as of the revision date. Prazosin does not affect serum prolactin concentration in patients with hypertension. The prolactin level in a mother with established lactation may not affect her ability to breastfeed.

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Protein Binding
Highly bound to proteins with 97% binding to albumin and alpha 1-acid glycoprotein. Prazosin is thought to be mostly (about 80-90%) bound 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 is a member of the class of piperazines that is piperazine substituted by a furan-2-ylcarbonyl group and a 4-amino-6,7-dimethoxyquinazolin-2-yl group at positions 1 and 4 respectively. It has a role as an antihypertensive agent, an alpha-adrenergic antagonist and an EC 3.4.21.26 (prolyl oligopeptidase) inhibitor. It is a member of piperazines, a member of quinazolines, a member of furans, a monocarboxylic acid amide and an aromatic ether.
Prazosin is a drug used to treat hypertension. Prazosin is marketed by Pfizer and was initially approved by the FDA in 1988. It belongs to the class of drugs known as alpha-1 antagonists. Recently, many studies have evaluated the benefits of this drug in controlling the symptoms of post-traumatic stress disorder (PTSD) and associated nightmares.
Prazosin is an alpha-Adrenergic Blocker. The mechanism of action of prazosin is as an Adrenergic alpha-Antagonist.
Prazosin is a nonselective alpha-adrenergic antagonist (alpha-blocker) used in the therapy of hypertension. Prazosin is associated with a low rate of transient serum aminotransferase elevations and has not been clearly linked to clinically apparent acute liver injury.
Prazosin is a synthetic piperazine derivative and an alpha-1 adrenergic receptor inhibitor used primarily as an anti-hypertensive. Prazosin's effects are most pronounced in the large resistance vessels (i.e. arterioles) and result in a decrease in total systemic vascular resistance (SVR) without a rebound or reflex tachycardia. To a lesser extent, this agent also decreases the tone of the bladder sphincter, thereby allowing the opening of the bladder into the urethra and thus relieving the urinary conditions associated with benign prostatic hypertrophy.
A selective adrenergic alpha-1 antagonist used in the treatment of HEART FAILURE; HYPERTENSION; PHEOCHROMOCYTOMA; RAYNAUD DISEASE; PROSTATIC HYPERTROPHY; and URINARY RETENTION.
See also: Prazosin Hydrochloride (has salt form).

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Drug Indication
This drug is indicated for the treatment of hypertension (high blood pressure). Prazosin can be given alone or given with other blood pressure-lowering drugs, including diuretics or beta-adrenergic blocking agents. Prazosin does not negatively impact lung function, and therefore may be used to manage hypertension in patients who are asthmatic or patients with chronic obstructive lung disease (COPD).
FDA Label

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Mechanism of Action
Alpha-adrenergic receptors are essential for the regulation of blood pressure in humans. Two types of alpha receptors, alpha 1 and alpha 2, both play a role in regulating blood pressure. Alpha-1 receptors are postsynaptic (located after the nerve junction, or space between a nerve fiber and target tissue). In this case, the target tissue is the vascular smooth muscle. These receptors, when activated, increase blood pressure. Prazosin inhibits the postsynaptic alpha-1 adrenoceptors. This inhibition blocks the vasoconstricting (narrowing) effect of catecholamines (epinephrine and norepinephrine) on the vessels, leading to peripheral blood vessel dilation. Through blood vessel constriction by adrenergic receptor activation, epinephrine and norepinephrine normally act to increase blood pressure.

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Pharmacodynamics
**Effects on blood pressure** The pharmacodynamic and therapeutic effect of this drug includes is a decrease in blood pressure as well as clinically significant decreases in cardiac output, heart rate, blood flow to the kidney, and glomerular filtration rate. The decrease in blood pressure may occur in both standing and supine positions. Many of the above effects are due to vasodilation of blood vessels caused by prazosin, resulting in decreased peripheral resistance,. Peripheral resistance refers to the level resistance of the blood vessels to blood that flows through them. As the blood vessels constrict (narrow), the resistance increases and as they dilate (widen), and peripheral resistance decreases, lowering blood pressure. **Effects on sleep disturbance related to post-traumatic stress disorder (PTSD)** Some studies have suggested that this drug improves sleep in patients suffering from insomnia related to nightmares and post-traumatic stress disorder, caused by hyperarousal. This effect likely occurs through the inhibition of adrenergic stimulation found in states of 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.)