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.

Binding experiments show that ZD 7155 is a potent angiotensin II type 1 receptor antagonist. In this study this novel substance was studied in normotensive and hypertensive rats. The relative potency and duration of the antihypertensive effects of ZD 7155 were compared with those of the reference substance, losartan. The inhibitory effects of both compounds on angiotensin II-induced pressor actions were studied in the conscious normotensive Sprague-Dawley (SD) rat and in the conscious, spontaneously hypertensive rat (SHR). Arterial blood pressure and heart rate (HR) were obtained by direct intraarterial recording. Angiotensin II infusion was administered intravenously in the dose range 53.3 ng-12.8 micrograms kg-1 min-1 to the conscious rats. ZD 7155 was administered in a bolus dose of 1.082 mumol kg-1 (0.51 mg kg-1) and losartan in bolus doses of 2.165 and 6.495 mumol kg-1 (1.0 and 3.0 mg kg-1). In conscious SD rats, ZD 7155 and losartan behaved as competitive antagonists and the pressor response curve to angiotensin II was shifted to the right. Experiments in conscious SD rats also showed that ZD 7155 was approximately ten times as potent as losartan in suppressing the angiotensin II-induced pressor response (240 ng kg-1; 10 min infusion). In addition, experiments with conscious rats demonstrated that ZD 7155 could suppress the angiotensin II-induced pressor response for approximately 24 h when ZD 7155 was administered intravenously in a 1.082 mumol kg-1 bolus dose and angiotensin II was given at 240 ng kg-1 (in a 10-min infusion). Experiments in conscious SHRs using ZD 7155 (1.082 mumol kg-1) and losartan (6.495 mumol kg-1) as intravenous boluses indicated that both ZD 7155 and the reference compound losartan exhibited a significant antihypertensive effect. These results demonstrate that ZD 7155 is a potent angiotensin II-type 1 antagonist which is approximately ten times as potent as losartan in suppressing the angiotensin II-induced pressor response. Furthermore, ZD 7155 may suppress the angiotensin II-induced pressor response for 24 h and in the SHR ZD 7155 induces a pronounced and persistent antihypertensive effect. [1]

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Experiments in conscious rats demonstrated that ZD 7155, in addition to its potent AT1 antagonistic effects, induced persistent suppression of the angiotensin 11-induced pressor response. Whereas ZD 7 155 significantly inhibited this response for approximately 24 h, the effects of losartan lasted for a considerably shorter time. ZD 7155 thus has the pharwcological profile of a potent and long-acting AT1 antagonist. Several selective synthetic AT1 antagonists are now avail- &le (MacFadyen & Reid 1994). Both competitive and noncompetitive agents have been developed and characterized. Unlike losartan, moreover, most of these compounds are not prodrugs. Structure-activity studies of the biphenylimidazole AT1 - aaugonists have demonstrated the importance of a free carMxylic acid functionality located at the ortho position of the aromatic ring. Replacement of this carboxyiic acid functionality with a negatively charged tetrazole as in losartan and ZD 7155 (Fig. I), will significantly enhance the affinity of he compounds for the AT1 receptor site (Chiu et a1 1990a, b). nm, as demonstrated by evidence from currently available selective AT1 antagonists, a hydrogen-donating or -accepting Wction seems to be critical for fhctional interaction with the AT1 receptor site. In the Sprague-Dawley rat model, ZD 7155 induced a pronounced and persistent antihypertensive effect. After single intravenous administrations ZD 7155 (1.082 pmol kg-') and losartan (6.495 pmol kg- I) both significantly reduced blood pressure in the SHR. The antihypertensive actions of the AT1 antagonists were seen as soon as 30 min after intravenous administration and significant and similar 1 &20% reductions of MAP remained after 6 h. Losartan and ZD 7155 are effective after peroral dosage (Oldham et a1 1993; Timmermans et a1 1993) and there is no development of tolerance to the antihypertensive action of losartan after repeated daily peroral dosing (Timmermans et a1 1993). In addition to reducing blood pressure, an AT1 antagonist such as losartan may inhibit the 'growth response' to angiotensin I1 in isolated smooth muscle cell preparations, because this response seems to be dependent on the AT1 receptor subtype (Timmermans et a1 1993). By analogy with the mgiotensin-converting enzyme inhibitors, blockade of the AT1 receptor site has also proven to be effective in reversing cardiac hypertrophy in animal models of hypertension (Timmermans et a1 1993). In conclusion, the data presented demonstrate that ZD 7155 acts as an AT1 receptor antagonist which is more potent in Suppressing the angiotensin 11-induced pressor response and Produces an antihypertensive effect in the SHR which is more Persistent than that of 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.)