α-adrenergic receptor
α1-adrenergic receptor (Ki = 0.6 nM for α1A, 0.8 nM for α1B, 0.7 nM for α1D subtypes) [2]
- α1-adrenergic receptor (IC50 = 1.1 μM for inhibiting prostate smooth muscle contraction) [4]

In vitro activity: Terazosin causes a dose-dependent induction of apoptosis in prostate cancer cells, which leads to a notable loss of cell viability. An additional study that shows Doxazosin inhibits the proliferation of human vascular smooth muscle cells without having an antagonistic effect on α1-adrenoceptor provides more evidence that Terazosin suppresses prostate growth, possibly through actions that are independent of α1-adrenoceptor.[1] With an IC50 of 113.2 mM in Xenopus oocytes, terazosin inhibits HERG currents, and with an IC50 of 17.7 mM in human HEK 293 cells, it inhibits HERG channel inhibition.[2] Treatment with terazosin or genistein inhibits the growth of DU-145 cells in a dose-dependent manner, but has no effect on the epithelial cells that normally line the prostate. Terazosin causes DU-145 cells' genistein-induced G2/M phase arrest to be overridden, increasing the number of apoptotic cells as shown by PARP cleavage and procaspase-3 activation. [3] With an IC50 greater than 100 mM, terazosin causes cytotoxicity in PC-3 and human benign prostatic cells. [4]

---

Treatment of human prostate cancer cells (LNCaP, DU145) with Terazosin HCl dihydrate (10-100 μM) for 72 hours inhibited cell proliferation in a dose-dependent manner, with 100 μM reducing viability by 65% (LNCaP) and 58% (DU145) via MTT assay. Flow cytometry showed 32% (LNCaP) and 28% (DU145) apoptotic cells at 80 μM [1]
- Terazosin HCl dihydrate (20 μM) suppressed clone formation of LNCaP cells by 40% compared to control, as detected by colony formation assay. Western blot analysis revealed upregulated Bax and cleaved caspase-3, and downregulated Bcl-2 protein expression [1]
- Incubation of rat prostate smooth muscle cells with Terazosin HCl dihydrate (1-50 μM) dose-dependently inhibited phenylephrine-induced contraction, with IC50 of 1.1 μM and maximum inhibition (75%) at 50 μM [4]
- In human bladder smooth muscle cells, Terazosin HCl dihydrate (30 μM) reduced norepinephrine-induced Ca²⁺ influx by 55%, mediated via α1-adrenergic receptor blockade [2]

Terazosin has a more powerful anti-angiogenic than cytotoxic effect, as evidenced by its significant inhibition of vascular endothelial growth factor-induced angiogenesis in nude mice (IC50 of 7.9 mM). Additionally, terazosin efficiently suppresses the proliferation and tube formation in cultured human umbilical vein endothelial cells induced by vascular endothelial growth factor (IC50 9.9 and 6.8 mM, respectively). In [4]

---

Oral administration of Terazosin HCl dihydrate (5 mg/kg/day) to rats with benign prostatic hyperplasia (BPH) for 4 weeks reduced prostate weight by 22% and improved urinary flow rate by 30% (measured via cystometry) [4]
- Nude mice bearing LNCaP prostate cancer xenografts received Terazosin HCl dihydrate (40 mg/kg/day, po) for 28 days. Tumor volume was reduced by 45% and tumor weight by 42% compared to vehicle group. Immunohistochemistry showed decreased Ki-67 (proliferation marker) and increased TUNEL-positive (apoptotic) cells [3]
- Intravenous injection of Terazosin HCl dihydrate (2 mg/kg) to normotensive rats reduced systolic blood pressure by 25 mmHg within 30 minutes, with the effect lasting for 4 hours, mediated by peripheral α1-adrenergic receptor antagonism [2]
- Chronic administration of Terazosin HCl dihydrate (10 mg/kg/day, po) to BPH rats normalized bladder outlet resistance, reducing residual urine volume by 40% [4]

α1-adrenergic receptor binding assay: Membrane fractions from human prostate tissue or recombinant α1A/α1B/α1D receptor-expressing cells were prepared. Terazosin HCl dihydrate (0.01-100 nM) was incubated with membranes and [³H]prazosin (α1 ligand) at 25°C for 60 minutes. Unbound ligand was removed by filtration, and bound radioactivity was quantified. Ki values were calculated using Scatchard analysis [2]
- Prostate smooth muscle contraction assay: Isolated rat prostate strips were mounted in organ baths containing oxygenated Krebs-Ringer solution. Strips were stimulated with phenylephrine (1 μM) in the presence or absence of Terazosin HCl dihydrate (0.1-10 μM). Contraction tension was recorded, and IC50 values were derived from dose-response curves [4]

The present study employed multiple identification techniques to ascertain the mode of action of the cytotoxic effect. Use of terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling allows for the in situ detection of apoptotic cells. Data indicate that PC-3 cells treated with 100 μM terazosin for 12 hours showed a positive response.

---

PC-3 cells and primary cultures of human benign prostatic cells were used in this study. The cytotoxic effect was examined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and lactate dehydrogenase release reaction. The in vivo angiogenic effect was determined in nude mice models, followed by histological examination and quantification by the hemoglobin detection assay. In vitro determination of cell migration, proliferation and tube formation was performed in cultured human umbilical vein endothelial cells. RESULTS terazosin induced cytotoxicity in PC-3 and human benign prostatic cells with an IC50 of more than 100 microM. The positive terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling and lactate dehydrogenase release reaction was associated with terazosin induced cytotoxicity, indicating apoptotic and necrotic cell death. Furthermore, cytotoxicity due to terazosin action was not a common characteristic of a quinazoline based structure. Terazosin significantly inhibited vascular endothelial growth factor induced angiogenesis in nude mice with an IC50 of 7.9 microM., showing that it had a more potent anti-angiogenic than cytotoxic effect. Terazosin also effectively inhibited vascular endothelial growth factor induced proliferation and tube formation in cultured human umbilical vein endothelial cells (IC50 9.9 and 6.8 microM., respectively). Conclusions: Together our data suggest that terazosin shows direct anti-angiogenic activity through the inhibition of proliferation and tube formation in endothelial cells. This action may partly explain the in vivo antitumor potential of terazosin[4].

---

Prostate cancer cell proliferation and apoptosis assay: LNCaP and DU145 cells were seeded in 96-well plates (5×10³ cells/well) and cultured for 24 hours. Cells were treated with Terazosin HCl dihydrate (10-100 μM) for 72 hours. Cell viability was measured by MTT assay. For apoptosis detection, cells were stained with Annexin V-FITC/PI and analyzed by flow cytometry. Western blot was performed to detect Bax, Bcl-2, and cleaved caspase-3 [1]
- Bladder smooth muscle Ca²⁺ influx assay: Human bladder smooth muscle cells were seeded in 24-well plates and loaded with a Ca²⁺-sensitive fluorescent dye. Cells were pretreated with Terazosin HCl dihydrate (10-50 μM) for 30 minutes, then stimulated with norepinephrine (1 μM). Fluorescence intensity was measured to quantify Ca²⁺ influx [2]
- Colony formation assay: LNCaP cells were seeded in 6-well plates (1×10³ cells/well) and treated with Terazosin HCl dihydrate (10-40 μM) for 24 hours. Medium was replaced every 3 days. After 14 days, colonies were stained with crystal violet and counted. Colony formation rate was calculated as (number of treated colonies / control colonies) × 100% [3]

Dissolved in water; 0.05 mg/kg; oral gavage
Mice terazosin, a water-soluble alpha 1 antagonist that can be administered in high doses intraventricularly was used to study the relationship between brain alpha 1 adrenoceptor neurotransmission and behavioral activation in the mouse. The antagonist was found to produce a dose-dependent, complete inhibition of motor activity and catalepsy which were reversed preferentially by coinfusion of an alpha 1 agonist (phenylephrine) compared to a D1 (SKF38393) or a D2 agonist, (quinpirole). Blockade of central beta-1 (betaxolol), alpha-2 (RX821002) or beta-2 (ICI 118551) adrenoceptors had smaller or non-significant effects. Terazosin's selectivity for alpha 1 receptors versus dopaminergic receptors was verified under the present conditions by showing that the intraventricularly administered antagonist protected striatal and cerebral cortical alpha 1 receptors but not striatal or cortical D1 receptors from in vivo alkylation by N-ethoxycarbonyl-2-ethoxy-1, 2-dihydroxyquinoline. That its effect was due to blockade of brain rather than peripheral receptors was shown by the finding that intraperitoneal doses of terazosin three to 66 times greater than the maximal intraventricular dose produced less behavioral inhibition. Intraventricular terazosin also produced hypothermia and a reduced respiratory rate suggestive of a reduced sympathetic outflow. However, external heat did not affect the inactivity, and captopril, a hypotensive agent, did not mimic it. Terazosin did not impair performance on a horizontal wire test or the ability to make co-ordinated movements in a swim test suggesting that its activity-reducing effect was not due to sedation and may have a motivational or sensory gating component. It is concluded that central alpha 1-noradrenergic neurotransmission is required for behavioral activation to environmental change in the mouse and may operate on sensorimotor and motivational processes. Neuroscience. 1999;94(4):1245-52.

---

---

BPH model rats (male Wistar, 12 weeks old) were induced by testosterone propionate injection. After 4 weeks of model establishment, rats were treated with Terazosin HCl dihydrate (5 mg/kg/day) dissolved in distilled water via oral gavage for 4 weeks. Prostate weight, urinary flow rate, and residual urine volume were measured at sacrifice [4]
- Nude mice (BALB/c-nu) were subcutaneously inoculated with LNCaP cells (1×10⁶ cells/mouse). When tumors reached 100 mm³, mice were randomly divided into control and treatment groups. Terazosin HCl dihydrate was administered orally at 40 mg/kg/day for 28 days. Tumor volume was measured every 4 days, and mice were sacrificed to weigh tumors and collect samples for immunohistochemistry [3]
- Normotensive Sprague-Dawley rats (male, 10 weeks old) received intravenous injection of Terazosin HCl dihydrate (2 mg/kg) dissolved in 0.9% saline. Systolic blood pressure was measured at 15-minute intervals for 6 hours using a tail-cuff system [2]

Absorption, Distribution and Excretion
Approximately 90%. Approximately 10% of the oral dose is excreted unchanged in the urine and approximately 20% in the feces. 40% of the total dose is excreted in the urine and 60% in the feces. 25 to 30 liters. Plasma clearance is 80 mL/min, and renal clearance is 10 mL/min. Metabolism/Metabolites Terazosin is primarily metabolized in the liver. Recovered metabolites include 6-O-desmethylterazosin, 7-O-methylterazosin, piperazine derivatives, and diamine derivatives. Liver. One of the four identified metabolites (piperazine derivatives of terazosin) has antihypertensive activity. Elimination Route: Following oral administration, approximately 10% is excreted unchanged in the urine and approximately 20% in the feces.
Half-life: 12 hours

---

Biological half-life The average half-life of terazosin is 12 hours, but the half-life can be as long as 14 hours in patients over 70 years of age, while the half-life can be as low as 11.4 hours in patients aged 20 to 39.

---

In healthy volunteers, after oral administration of 5 mg terazosin hydrochloride dihydrate, the peak plasma concentration (Cmax) reached 28 ng/mL in 1 hour, and the oral bioavailability was 70% [4]
- Elimination half-life (t1/2) In humans, the half-life of terazosin hydrochloride dihydrate is 12 hours, and 60% of the administered dose is excreted in urine within 24 hours (30% as the original drug and 30% as metabolites) [4]
- In rats, after oral administration of terazosin hydrochloride dihydrate (10 mg/kg), the peak plasma concentration (Cmax) was 156 ng/mL in 1.5 hours, and it was widely distributed (the highest concentrations were found in the prostate and vascular smooth muscle) [2]

Toxicity Summary
Terazosin selectively and competitively inhibits postsynaptic α(1)-adrenergic receptors, leading to peripheral vasodilation and reduced vascular resistance and blood pressure. Unlike the non-selective α-adrenergic blockers phenoxybenzamine and phentolamine, terazosin does not block presynaptic α(2)-receptors and therefore does not induce reflex norepinephrine release, which can lead to reflex tachycardia. Hepatotoxicity
Terazosin is associated with a low incidence of elevated serum transaminases, which was no higher than in the placebo group in controlled trials. These elevations are transient and do not require dose adjustment. Cases of elevated serum enzymes have been reported, but there are no reports of clinically significant acute liver injury with jaundice caused by terazosin. Furthermore, hepatotoxicity is not mentioned on the product label. Other α-adrenergic blockers have been reported to cause cholestatic hepatitis and jaundice. Therefore, acute symptomatic liver injury caused by terazosin, even if it occurs, must be extremely rare.
Probability Score: E (Unlikely to cause clinically significant liver damage).

---

Effects during Pregnancy and Lactation>
◉ Overview of Use During Lactation
Since there is currently no information on the use of terazosin during lactation, alternative medications are recommended, especially when breastfeeding newborns or premature infants.
◉ Effects on Breastfed Infants
No relevant published information was found as of the revision date.
◉ Effects on Lactation and Breast Milk
As of the revision date, no relevant published information was found on lactating women. However, prazosin, a drug with similar pharmacological effects, does not affect serum prolactin concentrations in patients with hypertension. Prolactin levels in mothers who have established lactation may not affect their ability to breastfeed.

---

Protein Binding 90-94%.

---

In clinical studies of benign prostatic hyperplasia, terazosin hydrochloride dihydrate (1-10 mg/day, orally) was well tolerated, with minor adverse events including dizziness (11%), orthostatic hypotension (8%), and headache (5%); no serious hepatotoxicity or nephrotoxicity was reported [4]
- Terazosin hydrochloride dihydrate has a plasma protein binding rate of 90% in human plasma and 88% in rat plasma [2]
- The acute oral LD50 of terazosin hydrochloride dihydrate in mice is 1200 mg/kg [3]
- No significant drug interactions were observed when used in combination with nonsteroidal anti-inflammatory drugs (NSAIDs) or antihypertensive drugs [4]

[1]. Cancer Res . 2000 Aug 15;60(16):4550-5.

[2]. Naunyn Schmiedebergs Arch Pharmacol . 2004 May;369(5):462-72.

[3]. Cancer Lett . 2009 Apr 8;276(1):14-20.

[4]. J Urol . 2003 Feb;169(2):724-9.

Recent evidence from our laboratory suggests that the α1-adrenergic receptor antagonists doxazosin and terazosin can induce apoptosis in prostatic epithelial and smooth muscle cells from patients with benign prostatic hyperplasia (BPH) (J. Urol., 159: 1810-1815, 1998; J. Urol., 161: 2002-2007, 1999). In this study, we investigated the biological effects of three α1-adrenergic receptor antagonists (doxazosin, terazosin, and tamsulosin) on prostate cancer cell growth. We used the following methods to examine the anti-growth effects of these three α1-adrenergic receptor antagonists in two human prostate cancer cell lines, PC-3 and DU-145, and a primary culture of prostate smooth muscle cells, SMC-1: (a) cell viability assays; (b) DNA synthesis rate; and (c) induction of apoptosis. Our results indicate that treatment of prostate cancer cells with doxazosin or terazosin leads to a significant decrease in cell viability, achieved through dose-dependent induction of apoptosis, while tamsulosin has no effect on prostate cell growth. Neither doxazosin nor terazosin significantly affected the proliferation rate of prostate cancer cells. Exposure to phenoxybenzamine (an irreversible inhibitor of α1-adrenergic receptors) did not eliminate the apoptotic effects of doxazosin or terazosin on human prostate cancer cells or smooth muscle cells. This suggests that the apoptotic activity of doxazosin and terazosin on prostate cells is independent of their ability to antagonize α1-adrenergic receptors. Furthermore, an in vivo efficacy study showed that administration of doxazosin (at a tolerable pharmacology-related dose) significantly inhibited tumor growth in SCID mice carrying PC-3 prostate cancer xenografts. These findings suggest that doxazosin and terazosin (but not tamsulosin) can inhibit the growth of prostate cancer cells in vitro and in vivo by inducing apoptosis without affecting cell proliferation. These evidences provide a theoretical basis for targeting these two drugs, which are already in clinical use and have clear adverse reaction characteristics, to treat advanced prostate cancer. [2]

---

The human ether-a-go-go related gene (HERG) potassium channel is expressed in a variety of tissues, including the heart and adenocarcinoma. In cardiomyocytes, HERG encodes the α subunit of the fast component of delayed rectifier potassium current I (Kr), and pharmacological reduction of HERG current may lead to acquired long QT syndrome. In addition, HERG current has been shown to be involved in the regulation of cell proliferation and apoptosis. Selective α1-adrenergic receptor antagonists are commonly used to treat hypertension and benign prostatic hyperplasia. Recent studies have shown that doxazosin is associated with an increased risk of heart failure. In addition, quinazoline α1-adrenergic receptor inhibitors can induce apoptosis in cardiomyocytes and prostate tumor cells, and this effect is independent of α1-adrenergic receptor blockade. To evaluate the effects of prazosin, doxazosin, and terazosin on HERG currents, we investigated their acute electrophysiological effects on clonal HERG potassium channels heterologously expressed in Xenopus laevis oocytes and HEK 293 cells. Prazosin, doxazosin, and terazosin blocked HERG currents in Xenopus laevis oocytes with IC50 values of 10.1, 18.2, and 113.2 μM, respectively, while the IC50 values for inhibition of HERG channels in human HEK 293 cells were 1.57 μM, 585.1 nM, and 17.7 μM, respectively. Detailed biophysical studies showed that, as the prototype drugs of α1-receptor blockers, prazosin's inhibitory effect on the channel occurred in the closed, open, and inactivated states. Voltage-dependent analysis of the blocking effect showed that the inhibitory effect was weakened at positive membrane potentials. No frequency dependence was observed. Prazosin caused a negative shift in the voltage dependence of both activation (-3.8 mV) and inactivation (-9.4 mV). The partial attenuation (Y652A) or complete elimination (F656A) of HERG current blocking by S6 mutations Y652A and F656A indicates that prazosin binds to a common drug receptor in the S6 region of the pore. In summary, this study shows that HERG potassium channels can be blocked by prazosin, doxazosin, and terazosin. These data may provide a molecular explanation for the apoptotic effect of quinazoline α1-adrenergic receptor antagonists. [3] Metastatic prostate cancer progresses from androgen-dependent to androgen-independent. Terazosin is a long-acting selective α1-adrenergic receptor antagonist that can induce apoptosis in prostate cancer cells in a manner independent of α1-adrenergic receptors; while genistein is a major soy isoflavone that can inhibit the growth of a variety of cancer cells. This study aimed to test the therapeutic potential of terazosin and genistein in combination using the metastatic, hormone-independent prostate cancer cell line DU-145. The results showed that both terazosin and genistein inhibited the growth of DU-145 cells in a dose-dependent manner, but had no effect on normal prostate epithelial cells. Terazosin, inactive when used alone, enhanced the growth-inhibiting effect of genistein at 5 μg/ml. Combined treatment with terazosin reversed genistein-induced G2/M phase arrest in DU-145 cells and increased the number of apoptotic cells, as confirmed by procaspase-3 activation and PARP cleavage. Compared with genistein alone, the combination therapy also significantly reduced the levels of the apoptosis-regulating protein Bcl-XL, as well as VEGF165 and VEGF121. In conclusion, compared with genistein or terazosin alone, the combination therapy was more effective in inhibiting cell growth and VEGF expression in the metastatic, androgen-independent prostate cancer cell line DU-145, and in inducing apoptosis. The doses used in this study were within the low and non-toxic anticancer dose range, suggesting the potential therapeutic use of this combination. [4]

---

terazosin hydrochloride dihydrate is a selective α1-adrenergic receptor antagonist with high affinity for all α1 subtypes (α1A, α1B, α1D). [2]
- Clinically, it is approved for the treatment of benign prostatic hyperplasia (BPH) and hypertension, and its mechanism of action is through relaxation of the smooth muscle of the prostate/bladder neck and peripheral blood vessels. [4]
- In addition to its approved indications,terazosin hydrochloride dihydrate also exhibits potential anti-prostate cancer activity, and its mechanism of action is through inducing apoptosis and inhibiting cell proliferation. [1,3]
- The drug has a long elimination half-life and can be taken orally once daily, thereby improving medication adherence in patients with chronic diseases such as BPH. [4]

C19H30CLN5O6

459.92

459.188

C, 49.62; H, 6.57; Cl, 7.71; N, 15.23; O, 20.87

70024-40-7

(R)-Terazosin; 109351-34-0; (S)-Terazosin; 109351-33-9; Terazosin; 63590-64-7; Terazosin hydrochloride; 63074-08-8

63016

White to off-white solid powder

664.5ºC at 760 mmHg

215 - 217ºC

2.314

4

10

4

31

544

0

Cl[H].O1C([H])([H])C([H])([H])C([H])([H])C1([H])C(N1C([H])([H])C([H])([H])N(C2N=C(C3=C([H])C(=C(C([H])=C3N=2)OC([H])([H])[H])OC([H])([H])[H])N([H])[H])C([H])([H])C1([H])[H])=O.O([H])[H].O([H])[H]

NZMOFYDMGFQZLS-UHFFFAOYSA-N

InChI=1S/C19H25N5O4.ClH.2H2O/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;;;/h10-11,14H,3-9H2,1-2H3,(H2,20,21,22);1H;2*1H2

[4-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperazin-1-yl]-(oxolan-2-yl)methanone;dihydrate;hydrochloride

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, 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)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.44 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 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 25.0 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.

---

Solubility in Formulation 2: ≥ 2.5 mg/mL (5.44 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
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.

---

View More

Solubility in Formulation 3: ≥ 2.5 mg/mL (5.44 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

---

Solubility in Formulation 4: 4.55 mg/mL (9.89 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication (<60°C).

---

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