Angiotensin II receptor type 1 (AT1 receptor)

This study has demonstrated that ZD 7155 is a potent competitive AT1 antagonist. Using losartan as a reference AT1 receptor antagonist we found that ZD 7 155 was approximately ten times more potent than losartan in antagonizing angiotensin 11-induced pressor effects. Binding experiments on guinea-pig adrenal gland membranes have demonstrated that ZD 7155 displaces ('251)-angiotensin I1 from its binding sites in a concentration-dependent manner (Wong et a1 1992). Further, in the isolated guinea-pig ileum, ZD 7155 potently shifted the angiotensin I1 dose-response curve to the right with a marked depression of the maximum response (Oldham et al 1993) [1].

ZD 7155 and losartan act as competitive antagonists in conscious SD rats, which causes angiotensin II's pressor response curve to move to the right. ZD 7155 was also around ten times more effective than losartan (240 ng/kg; 10 min infusion) at suppressing the angiotensin II-induced pressor response, according to experiments conducted on awake SD rats. Additionally, a study conducted on conscious rats revealed that a bolus dose of 1.082 μmol/kg of ZD 7155 and 240 ng/kg of angiotensin II were given intravenously (during a 10-minute infusion period). Studies with intravenous boluses of ZD 7155 (1.082 mumol/kg) and losartan (6.495 mumol/kg) in awake SHR revealed that both compounds had notable antihypertensive effects Function[1].

‌Experimental Setup:‌[1]
‌Animal Model:‌ Sprague-Dawley rats were used in the study.
‌Control Treatment:‌ Saline was administered as the control for comparison with angiotensin II type 1 receptor antagonists.
‌Drug Administration:‌
ZD 7155 was given intravenously as a bolus dose of ‌1.082 pmol/kg‌.
‌Losartan‌ was administered at two different doses: ‌2.165 pmol/kg‌ and ‌6.495 pmol/kg‌.

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Experimental protocol [1]
The cardiotachograph triggered by the arterial pulse recorded HR in beats min-I. By means of these data the increase of mean basal blood pressure to maximum peak height was analysed and presented as the difference between the mean arterial blood pressure values (AMAP). The duration of the pressor response was also analysed. Angiotensin I1 was used in all experiments. angiotensin I1 was dissolved in saline containing 0.5% bovine serum albumin and administered as a 10-min infusion via the intravenous catheter. In the dose-range experiments, angiotensin I1 was infused in incremental doses from 53.3 ng to 12.8 pg kg-' min-l with 30-min intervals. Five incremental doses were studied for each of the AT1 receptor antagonists in groups of 3-6 animals dose-'. The inhibitory effects of the AT1 receptor antagonists ZD 7155 and losartan on angiotensin I1 (240 ng kg-')-induced increases in MAP and basal blood pressure were assessed. ZD 7155 was administered in an intravenous bolus dose of 1.082 pmol kg-' (0.51 mg kg-I) into the jugular vein of conscious SpragueDawley rats. For the reference compound losartan, intravenous bolus doses of 2.165 to 6.495 pmol kg- I (1 .O to 3.0 mg kg- ') were used. Saline served as a control for ZD 7155 and losartan. For each dose level of the AT1 antagonists, groups of seven animals were analysed. The AT1 antagonists were administered 5 min before the first dose of angiotensin 11 [1].

[1]. Comparative cardiovascular effects of the angiotensin II type 1 receptor antagonists ZD 7155 and losartan in the rat. J Pharm Pharmacol. 1996 Aug;48(8):829-33.

Combined experimental results indicate that ZD 7155 is a potent angiotensin II type 1 receptor antagonist. This study investigated this novel compound in normotensive and hypertensive rats. The antihypertensive efficacy and duration of action of ZD 7155 were compared with those of the reference drug losartan. The inhibitory effects of these two compounds on angiotensin II-induced pressor effects were investigated in conscious normotensive Sprague-Dawley (SD) rats and conscious spontaneously hypertensive rats (SHR). Arterial blood pressure and heart rate (HR) were obtained by direct intra-arterial recording. Angiotensin II was administered intravenously to conscious rats at doses ranging from 53.3 ng to 12.8 μg kg⁻¹ min⁻¹. ZD 7155 was administered as a single intravenous dose of 1.082 μmol kg⁻¹ (0.51 mg kg⁻¹), while losartan was administered as single intravenous doses of 2.165 and 6.495 μmol kg⁻¹ (1.0 and 3.0 mg kg⁻¹). In conscious SD rats, both ZD 7155 and losartan acted as competitive antagonists, shifting the angiotensin II pressor response curve to the right. Experiments in conscious SD rats also showed that ZD 7155 was approximately ten times more potent than losartan in inhibiting the angiotensin II-induced pressor response (240 ng kg⁻¹; 10-minute infusion). Furthermore, experiments in conscious rats showed that when ZD 7155 was administered intravenously at a dose of 1.082 μmol kg⁻¹ and angiotensin II was infused intravenously at a dose of 240 ng kg⁻¹ (continuous infusion over 10 minutes), ZD 7155 inhibited the angiotensin II-induced pressor response for approximately 24 hours. Experiments in conscious spontaneously hypertensive rats (SHR) showed that intravenous administration of ZD 7155 at a dose of 1.082 μmol kg⁻¹ and losartan (6.495 μmol kg⁻¹) both significantly reduced blood pressure. These results indicate that ZD 7155 is a potent angiotensin II type 1 receptor antagonist, with an inhibitory potency approximately ten times that of losartan in inhibiting the angiotensin II-induced pressor response. In addition, ZD 7155 inhibits the angiotensin II-induced pressor response for up to 24 hours and produces a significant and sustained antihypertensive effect in spontaneously hypertensive rats (SHR). [1] Experiments in conscious rats showed that ZD 7155, in addition to its potent AT1 receptor antagonism, also sustainedly inhibits the angiotensin II-induced pressor response. ZD 7155 significantly inhibited the response for about 24 hours, while the duration of action of losartan was significantly shorter. Therefore, ZD 7155 has the pharmacological characteristics of a potent and long-acting AT1 receptor antagonist. Several selectively synthesized AT1 receptor antagonists are currently available (MacFadyen & Reid 1994). Both competitive and non-competitive drugs have been developed and characterized. In addition, unlike losartan, most of these compounds are not prodrugs. Structure-activity relationship studies of bifenimazole AT1 receptor agonists have shown that the free carboxyl functional group located ortho to the aromatic ring is crucial. As demonstrated in losartan and ZD 7155 (Figure I), replacing this carboxyl functional group with a negatively charged tetrazolium group significantly enhances the affinity of the compound for the AT1 receptor site (Chiu et al., 1990a, b). As demonstrated by existing selective AT1 receptor antagonists, the hydrogen donor or acceptor group appears to be essential for functional interaction with the AT1 receptor site. In the Sprague-Dawley rat model, ZD 7155 induced a significant and durable hypotensive effect. A single intravenous injection of ZD 7155 (1.082 pmol kg⁻¹) and losartan (6.495 pmol kg⁻¹) both significantly reduced blood pressure in spontaneously hypertensive rats (SHR). The antihypertensive effect of AT1 receptor antagonists can be observed as early as 30 minutes after intravenous injection, and mean arterial pressure (MAP) remains significantly reduced by 1% and 20% after 6 hours, with similar magnitudes. Oral administration of losartan and ZD 7155 is also effective (Oldham et al., 1993; Timmermans et al., 1993), and repeated daily oral administration of losartan does not induce tolerance (Timmermans et al., 1993). In addition to lowering blood pressure, AT1 receptor antagonists (such as losartan) may inhibit the “growth response” of isolated smooth muscle cells to angiotensin I1, as this response appears to depend on the AT1 receptor subtype (Timmermans et al., 1993). Similar to angiotensin-converting enzyme inhibitors, blocking the AT1 receptor site has also been shown to effectively reverse cardiac hypertrophy in hypertensive animal models (Timmermans et al., 1993). In summary, the data in this paper demonstrate that ZD 7155, as an AT1 receptor antagonist, is more effective in inhibiting the angiotensin I1-induced pressor response and produces a more sustained antihypertensive effect in spontaneously hypertensive rats (SHR) than the reference compound losartan.

C26H27CLN6O

474.9852

474.193

C, 65.75; H, 5.73; Cl, 7.46; N, 17.69; O, 3.37

146709-78-6

151801-76-2

9826191

White to yellow solid powder

746.4ºC at 760mmHg

405.2ºC

3.75E-22mmHg at 25°C

5.399

2

5

6

34

653

0

NAGGAAHTUXEGFG-UHFFFAOYSA-N

InChI=1S/C26H26N6O.ClH/c1-3-19-15-24-22(23(4-2)27-19)13-14-25(33)32(24)16-17-9-11-18(12-10-17)20-7-5-6-8-21(20)26-28-30-31-29-26;/h5-12,15H,3-4,13-14,16H2,1-2H3,(H,28,29,30,31);1H

5,7-diethyl-1-[[4-[2-(2H-tetrazol-5-yl)phenyl]phenyl]methyl]-3,4-dihydro-1,6-naphthyridin-2-one;hydrochloride

146709-78-6; ZD 7155 hydrochloride; ZD 7155(hydrochloride); 151801-76-2; zd7155; ZD7155 hydrochloride; 1,6-Naphthyridin-2(1H)-one, 5,7-diethyl-3,4-dihydro-1-[[2'-(2H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-, hydrochloride (1:1); 5,7-DIETHYL-3,4-DIHYDRO-1-[[2'-(1H-TETRAZOL-5-YL)[1,1'-BIPHENYL]-4-YL]METHYL]-1,6-NAPHTHYRIDIN-2(1H)-ONE 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)

DMSO : ~250 mg/mL (~526.33 mM)
H2O : ~4.17 mg/mL (~8.78 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (4.38 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 20.8 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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Solubility in Formulation 2: ≥ 2.08 mg/mL (4.38 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 20.8 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.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (4.38 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 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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