Cell lines

Neuro-2aneuroblastoma cells

Preparation Method

Neuro-2a cells were incubated for 24-h in a 37 ℃ incubator, and then treated for another 24-h with designed concentrations of PD123319. Optical density (OD) was measured at 570 nm.

Reaction Conditions

100μM PD123319 for 24 hours

Applications

Significant reduction in cell viability was observed when Neuro-2a cells were treated with the concentration of PD123319 (100 μM).

Animal models

LDL receptor -/- mice that were either wild type or deficient for AT2 receptors

Preparation Method

Osmotic minipumps were implanted subcutaneously to deliver saline, AngII (500 ng/kg/min), or PD123319 (3 mg/kg/d )

Dosage form

Osmotic minipump, 3 mg/kg/d

Applications

PD123319 acts through an angiotensin type 2(AT2) receptor-independent mechanism in angiotensin II -induced vasoconstriction in mice. PD123319 significantly increased Ang II-induced suprarenal aortic (AAAs) independent of AT2 receptors.

PD123319 is a non-peptide inhibitor of angiotensin II receptor with IC₅₀value of 34nM^[1].

PD123319 is an antagonist of angiotensin II receptor, unlike previous drugs act as inhibitors of the formation of Ang II. PD123319 shows inhibition potency in both rat adrenal and brain binding assay with IC₅₀values of 34nM and 210nM, respectively. It is found to prevent Ang II from binding the bovine zona glomerulosa microsomal preparation with IC₅₀value of 6.9nM in the binding assay using microsome.^[2,3]. PD123319 inhibited AT2 amplification product from rat pheochromocytoma cells (PC12w) binding to 0.5 nM 125I-[Sar1, Ile8]-Ang II with IC₅₀values of 1.7±0.2 nM^[4].In addition, it is reported that administration of PD123319 can suppress the generation of cyclic guanosine monophosphate and increase the production of prostaglandin E2^[2,3].

PD123319 was transfused intra-brachial arterial in healthy young volunteers to investigated forearm vascular responses and systemic blood pressure responses. There are significant increases in mean arterial pressure were observed during intra-brachial arterial infusions of PD123319 (p = 0.003) during both placebo (80±9 to 92±17 mmHg) and telmisartan (80±11 to 90±14 mmHg) therapy, possibly in locations other than the forearm resistance vessels. Intra-brachial arterial infusion of PD123319 (10 μg/min) has significant systemic effects on rising mean arterial pressure^[5].

References:
[1] Blankley C J, Hodges J C, Klutchko S R, et al. Synthesis and structure-activity relationships of a novel series of non-peptide angiotensin II receptor binding inhibitors specific for the AT2 subtype. Journal of medicinal chemistry, 1991, 34(11): 3248-3260.
[2] Boulay G, Servant G, Luong T T, et al. Modulation of angiotensin II binding affinity by allosteric interaction of polyvinyl sulfate with an intracellular domain of the DuP-753-sensitive angiotensin II receptor of bovine adrenal glomerulosa. Molecular pharmacology, 1992, 41(4): 809-815.
[3] Siragy H. Angiotensin II receptor blockers: review of the binding characteristics. The American journal of cardiology, 1999, 84(10): 3-8.
[4] Kambayashi, Y., Takahashi, K., Bardhan, S. et al. Molecular structure and function of angiotensin type2 receptor, Kidney Inr, 1994, 46, 1502- 1504.
[5] Daugherty A, Rateri DL, Howatt DA, Charnigo R, Cassis LA. PD123319 augments angiotensin II-induced abdominal aortic aneurysms through an AT2 receptor-independent mechanism. PLoS One. 2013; 8:e61849. doi: 10.1371/journal.pone.0061849.