α-adrenoceptor

In vitro activity: Tolazoline is a pulmonary vasodilator that is recommended for use in persistent pulmonary hypertension of the newborn (PPHN) to reduce pulmonary vascular resistance (PVR). Tolazoline exhibits both histamine agonist and modest alpha-adrenergic blocking properties. Vascular resistance and pulmonary arterial pressure are typically decreased by tolazoline.[1] Compared to SNP, tolazoline is less broadly effective against all spasmogens that have been studied. However, in human radial arteries, it might be useful in preventing vasospasm mediated by alpha-adrenoceptors.[2]

---

In vitro activity: Tolazoline (Imidaline) can be produced by heterocycling ethylene diamine with the ethyl ester of iminophenzylacetic acid to yield the desired product. Tolazoline (Imidaline) shares a structure with α-adrenergic agonists, which are sympathomimetics that reduce edema.

Studies have investigated the pharmacologic mechanism of 2-(4'-isothiocyanatobenzyl) imidazoline (IBI) and analogs for interaction with imidazoline receptors (IRs), alpha-adrenergic receptors (alpha-ARs), and calcium channels in cardiovascular muscle systems. IBI differs from tolazoline by substitution of an electrophilic isothiocyanato (NCS) group. Unlike tolazoline, which is a partial alpha-AR agonist, IBI produced an irreversible, slow-onset, and sustained contraction of rat aorta with an median effective concentration (EC50) value of 5 microM, and a maximal contraction (116%) greater than that of phenylephrine (100%) and tolazoline (59%). The IBI-induced contractions were dependent on calcium channels and independent of alpha-ARs or IRs. Similarly, structure-activity relation studies in rat aortic smooth muscles on a series of synthesized IBI analogs indicated that NCS analogs, but not those without the NCS group, exhibited effects by a non-alpha-AR, non-IR, but a calcium channel-dependent mechanism. Thus the presence of an intact IBI ring in these analogs is not a requirement for these activities. Further, IBI inhibited dihydropyridine (DHP, [3H]PN 200-110 and [3H]Bay K 8644) binding to L-type calcium channels of T-tubule membranes in rabbit skeletal muscle. In contrast to nifedipine, IBI and NCS derivatives (nifedipine-NCS, naphazoline-NCS) only partially (50-88%) displaced specific binding of these radioligands. A single site of noncooperative interaction was observed for nifedipine (nH = 0.97), whereas tolazoline-NCS (IBI, nH = 1.46) and nifedipine-NCS (nH = 1.37) exhibited a positive cooperativity in binding to DHP sites. These receptor-binding data indicate that NCS derivatives bind to L-type calcium channels and interact allosterically with DHP-binding sites. Direct binding of the NCS group to specific nucleophilic protein sites of the calcium channel may be responsible for its activation and the subsequent contractile effects of IBI. [1]

Tolazoline (10(-9)-10(-4) M) or sodium nitroprusside (SNP, 10(-9)-10(-4) M) were cumulatively applied on radial artery rings precontracted submaximally with noradrenaline, endothelin-1, thromboxane analogue, U46619, or potassium chloride. In addition, some rings were pretreated with tolazoline (4 x 10(-6) M) for 30 minutes and the contractile response curve to noradrenaline was assessed in its presence. Results: tolazoline effectively reversed noradrenaline-induced contractions in the radial artery, whereas it failed to produce remarkable relaxations on rings contracted with other spasmogenic agents, while SNP overcame the contractions induced by all spasmogens to a similar extent. In addition, brief pretreatment of radial artery rings with tolazoline significantly inhibited the contractions to noradrenaline. Conclusions: tolazoline is not as broadly effective as SNP against all spasmogens investigated; however, it may be effective in counteracting alpha-adrenoceptor-mediated vasospasm in human radial arteries. [2]

Infant TDLo IV 48 mg/kg/47H-C Gastrointestinal: Duodenal ulcer or hemorrhage; Gastrointestinal: Small bowel ulcer or hemorrhage, Australian Journal of Paediatrics, 22(221), 1986 [PMID:3767790]
Human TDLo IV 150 ug/kg Cardiac: Heart rate changes; Vascular: Other changes; Skin and its appendages (skin): Sweating: Other, Folia Medica, 27(729), 1941
Rats Oral LD50 1200 mg/kg Drugs in Japan, 6(511), 1982
Rats Intraperitoneal LD50 100 mg/kg Drugs in Japan, 6(511), 1982
Rats Intravenous LD50 85 mg/kg Drugs in Japan, 6(511), 1982

[1]. J Cardiovasc Pharmacol. 1998 May;31(5):721-33.

[2]. Ann Thorac Surg. 2006 Jan;81(1):125-31.

Tolazoline is an imidazole compound with the structure 4,5-dihydro-1H-imidazole substituted with a benzyl group. It has dual action as an α-adrenergic antagonist, antihypertensive, and vasodilator. Tolazoline is a vasodilator that apparently has a direct effect on blood vessels and increases cardiac output. Tolazoline can interact to some extent with histamine receptors, adrenergic receptors, and cholinergic receptors, but its therapeutic mechanism is unclear. It is used to treat persistent pulmonary hypertension in newborns. See also: Tolazoline hydrochloride (salt form). Drug Indications For the treatment of pulmonary artery malformations. Mechanism of Action Tolazoline dilates blood vessels through direct action on peripheral vascular smooth muscle and indirectly through the release of endogenous histamine; it possesses moderate α-adrenergic blocking activity and histamine agonist activity. Tolazoline typically reduces pulmonary artery pressure and vascular resistance. Tolazoline hydrochloride belongs to the benzene family. It is a vasodilator that apparently has a direct effect on blood vessels and increases cardiac output. Tolazoline interacts to some extent with histamine, adrenergic, and cholinergic receptors, but the mechanism of its therapeutic effect is unclear. It is used to treat persistent pulmonary hypertension in newborns. See also: Tolazoline (containing the active ingredient). The radial artery is increasingly used for coronary revascularization as an alternative vessel for great saphenous vein transplantation. Its good endothelial function makes its patency comparable to that of the internal mammary artery (IMA). However, its spastic nature makes intraoperative preparation difficult and may lead to early transplant failure postoperatively. Therefore, the use of effective vasodilators to treat and/or prevent radial artery spasm is crucial for prolonging the lifespan of transplanted vessels. Endogenous vasoconstrictors, including norepinephrine, endothelin-1, and thromboxane A2, may play a role in the pathogenesis of transplanted vessel spasm. In this study, we evaluated the vasodilatory effect of the non-selective α-adrenergic receptor blocker torazoline on vasodilation induced by various spasmotropic agents in isolated human radial arteries. [2]

C10H12N2

160.21

160.1

C, 74.97; H, 7.55; N, 17.48

59-98-3

Tolazoline hydrochloride; 59-97-2

5504

White to off-white solid powder

1.1±0.1 g/cm3

338.2±21.0 °C at 760 mmHg

66-69 °C(lit.)

158.3±22.1 °C

0.0±0.7 mmHg at 25°C

1.596

2.65

1

1

2

12

169

0

N1([H])C([H])([H])C([H])([H])N=C1C([H])([H])C1C([H])=C([H])C([H])=C([H])C=1[H]

JIVZKJJQOZQXQB-UHFFFAOYSA-N

InChI=1S/C10H12N2/c1-2-4-9(5-3-1)8-10-11-6-7-12-10/h1-5H,6-8H2,(H,11,12)

2-benzyl-4,5-dihydro-1H-imidazole

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)

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.

---

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).

View More

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)

---

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).

View More

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

---

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.

---

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