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Chemical Compound Review

AC1NSKGZ     (3S)-9-[(4-amino-3-methyl- phenyl)methyl]-4...

Synonyms: CHEMBL292277, SureCN9132716, CHEBI:196581, PD123177, NCGC00162092-01, ...
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Disease relevance of PD123177

  • The AII receptors were characterized by means of the subtype-specific receptor antagonists DuP 753 (AII-1) and PD123177 (AII-2) using changes of [Ca2+]i (fura-2) as an indirect measurement of vasoconstriction and of [3H]leucine or [3H]thymidine incorporation as indices for hypertrophy and hyperplasia, respectively [1].

High impact information on PD123177

  • The effect of Ang IV (10 nM) was not inhibited by Dup 753 (1.0 microM), a highly specific antagonist of the AT1 receptor, or by PD123177 (1.0 microM), a highly specific antagonist of the AT2 receptor [2].
  • The highly abundant angiotensin II receptors were shown to be AT2 by the marked reduction in radioligand binding achieved with PD123177 (10(-7)M), a specific AT2 receptor antagonist, whereas DuP 753 (10(-5)M), an AT1 receptor antagonist, had little effect [3].
  • In astrocyte cultures, competition of 125I-labeled AII (125I-AII) specific binding with AT1 (DuP753) or AT2 (PD123177, CGP42112A, [Phe(p-NH2)6]AII) selective receptor ligands revealed a potency series of AII greater than DuP753 much greater than CGP42112A greater than [Phe(p-NH2)6]AII greater than PD123177 [4].
  • Also, in astrocyte cultures, AII stimulated increases in inositolphospholipid hydrolysis that were significantly reduced by the AT1 receptor antagonist DuP753 but not altered by the AT2 receptor antagonist PD123177 [4].
  • In cells coexpressing AT(1) and AT(2) receptors, Ang II-induced phosphorylation of the AT(2) receptor was reduced by either PD123177 or the AT(1) receptor antagonist, DuP753, and was abolished by treatment with both antagonists or with PKC inhibitors [5].

Biological context of PD123177

  • In contrast, a second nonpeptide AII ligand, PD123177, did not compete for [3H]AII binding sites [6].
  • Losartan (DuP 753), an AT1 receptor antagonist, inhibited binding (IC50, 10.9 +/- 0.9 nM), whereas the AT2 receptor antagonist PD123177 did not [7].
  • In contrast, blockade of the AT(2) receptor by the selective AT(2) antagonist, PD123177 (10(-6) M), resulted in a pronounced down regulation of FN mRNA 9 h after the stimulation [8].
  • In contrast to GR117289, the AT2 receptor antagonist, PD123177 (20 micrograms kg-1 min-1 intra-renal artery; i.r.a.) caused no significant change in blood pressure, renal blood flow, or sodium and urine excretion, indicating that the renal effects of endogenous AII in these salt-replete animals are mediated predominantly by AT1 receptors [9].
  • Although downstream reabsorptive elements compensate for the powerful action of PD123177 in the earliest segment of the nephron, we also showed, using free-flow micropuncture and clearance techniques, that PD123177 induces a substantial diuresis, natriuresis and chloruresis, again similar in magnitude to DuP 753 [10].

Anatomical context of PD123177

  • In the isolated perfused rat adrenal gland, DuP 753 at 10(-6) and 10(-4) M but not PD123177 at 10(-3) M blocked the AII-induced epinephrine secretion [11].
  • DuP 753 and PD123177 are two nonpeptide angiotensin II (AII)-specific ligands, which show high affinities for two respective and distinct subtypes of AII binding sites, i.e., AII-1 and AII-2 sites, respectively, in the rat adrenal gland, brain and uterus [11].
  • In the whole brain, thalamus-septum and midbrain, PD123177 inhibited 90% of the specific binding with Ki value of 7.77 x 10(-8) M, 8.21 x 10(-8) M and 4.93 x 10(-8) M, respectively while DuP 753 had little effect [12].
  • Three treatments were given intraventricularly (i.v.t.), in 2 microliters artificial cerebrospinal fluid (ACSF) at 30 min intervals: (1) 50 ng Ang II, (2) 0.7 micrograms AT1 antagonist Losartan or 7.0 micrograms AT2 antagonist PD123177, followed by 50 ng Ang II, and (3) 50 ng Ang II, to test for recovery [13].
  • Radioligand binding studies on membranes of epidermis, dermis, and subdermal tissues confirmed the localization of receptors to these regions and displacement of binding by PD123177 showed the receptor was AT2 [14].

Associations of PD123177 with other chemical compounds


Gene context of PD123177

  • AII was displaced by the AT1-specific antagonist, DuP753 with a Ki of 17.37 +/- 1.49 nM, but not by the AT2 receptor analogues CGP42771B or PD123177 [20].
  • On the other hand, the increase of P450aldo induced by the low Na diet was not affected by an AT2-specific antagonist, PD123177 [21].
  • PD123177 (an AT2 selective antagonist) had no effect on binding [16].
  • Pretreatment with losartan or PD123177 significantly interfered with this AngII-induced immunoreactivity while divalanal-AngIV did not [22].
  • Two high-affinity receptor subtypes have been identified by radioligand binding with antagonists: losartan (DuP 753/MK954) identifies AT1 receptors; PD123177 and CGP42112A are markers for AT2 receptors [23].

Analytical, diagnostic and therapeutic context of PD123177

  • Angiotensin II (AT) receptor subtypes (AT1, selectively displaced by DuP 753, and AT2, selectively displaced by PD123177 and CGP42112A) were characterized by quantitative autoradiography after incubation with the AT agonist 125I-Sar1-AT, in specific brain nuclei of young (2-week-old) rats [24].
  • Physiological studies in which test compounds were injected into the internal carotid of the rat and cerebral blood flor (CBF) was measured by laser Doppler flowmetry indicated that pretreatment with Divalinal-Ang IV, but not DuP 753 or PD123177, blocked the increased flow observed with Ang IV infusion [25].


  1. Angiotensin II-1 receptors mediate both vasoconstrictor and hypertrophic responses in rat aortic smooth muscle cells. Chiu, A.T., Roscoe, W.A., McCall, D.E., Timmermans, P.B. Receptor (1991) [Pubmed]
  2. Angiotensin induction of PAI-1 expression in endothelial cells is mediated by the hexapeptide angiotensin IV. Kerins, D.M., Hao, Q., Vaughan, D.E. J. Clin. Invest. (1995) [Pubmed]
  3. Expression of AT2 receptors in the developing rat fetus. Grady, E.F., Sechi, L.A., Griffin, C.A., Schambelan, M., Kalinyak, J.E. J. Clin. Invest. (1991) [Pubmed]
  4. Angiotensin II receptor subtypes are coupled with distinct signal-transduction mechanisms in neurons and astrocytes from rat brain. Sumners, C., Tang, W., Zelezna, B., Raizada, M.K. Proc. Natl. Acad. Sci. U.S.A. (1991) [Pubmed]
  5. Homologous and heterologous phosphorylation of the AT(2) angiotensin receptor by protein kinase C. Olivares-Reyes, J.A., Jayadev, S., Hunyady, L., Catt, K.J., Smith, R.D. Mol. Pharmacol. (2000) [Pubmed]
  6. Angiotensin II receptor recognized by DuP753 regulates two distinct guanine nucleotide-binding protein signaling pathways. Crawford, K.W., Frey, E.A., Cote, T.E. Mol. Pharmacol. (1992) [Pubmed]
  7. Angiotensin-II-binding sites on hepatocyte nuclei. Booz, G.W., Conrad, K.M., Hess, A.L., Singer, H.A., Baker, K.M. Endocrinology (1992) [Pubmed]
  8. Differential regulation of thrombospondin-1 and fibronectin by angiotensin II receptor subtypes in cultured endothelial cells. Fischer, J.W., Stoll, M., Hahn, A.W., Unger, T. Cardiovasc. Res. (2001) [Pubmed]
  9. Role of angiotensin AT1 and AT2 receptors in mediating the renal effects of angiotensin II in the anaesthetized dog. Clark, K.L., Robertson, M.J., Drew, G.M. Br. J. Pharmacol. (1993) [Pubmed]
  10. Comparison of inhibitory potency by nonpeptide angiotensin II receptor antagonists PD123177 and DuP 753 on proximal nephron and renal transport. Cogan, M.G., Liu, F.Y., Wong, P.C., Timmermans, P.B. J. Pharmacol. Exp. Ther. (1991) [Pubmed]
  11. Functional studies of nonpeptide angiotensin II receptor subtype-specific ligands: DuP 753 (AII-1) and PD123177 (AII-2). Wong, P.C., Hart, S.D., Zaspel, A.M., Chiu, A.T., Ardecky, R.J., Smith, R.D., Timmermans, P.B. J. Pharmacol. Exp. Ther. (1990) [Pubmed]
  12. Regional distribution of the two subtypes of angiotensin II receptor in rat brain using selective nonpeptide antagonists. Leung, K.H., Smith, R.D., Pieter, n.u.l.l., Timmermans, B.M., Chiu, A.T. Neurosci. Lett. (1991) [Pubmed]
  13. The role of angiotensin, AT1 and AT2 receptors in the pressor, drinking and vasopressin responses to central angiotensin. Hogarty, D.C., Speakman, E.A., Puig, V., Phillips, M.I. Brain Res. (1992) [Pubmed]
  14. Expression of AT2 receptors in rat fetal subdermal cells. Grady, E.F., Kalinyak, J.E. Regul. Pept. (1993) [Pubmed]
  15. Angiotensin II receptor binding following myocardial infarction in the rat. Sun, Y., Weber, K.T. Cardiovasc. Res. (1994) [Pubmed]
  16. AT1 receptors mediate the release of prostaglandins in porcine smooth muscle cells and rat astrocytes. Leung, K.H., Chang, R.S., Lotti, V.J., Roscoe, W.A., Smith, R.D., Timmermans, P.B., Chiu, A.T. Am. J. Hypertens. (1992) [Pubmed]
  17. Regulatory role of angiotensin II on progesterone production by cultured human granulosa cells. Expression of angiotensin II type-2 receptor. Johnson, M.C., Vega, M., Vantman, D., Troncoso, J.L., Devoto, L. Mol. Hum. Reprod. (1997) [Pubmed]
  18. Nonpeptide angiotensin II receptor antagonists. Studies with DuP 753 and EXP3174 in dogs. Wong, P.C., Hart, S.D., Duncia, J.V., Timmermans, P.B. Eur. J. Pharmacol. (1991) [Pubmed]
  19. Characterization of cardiac angiotensin AT1 receptors by [3H]SR 47436. Delisée, C., Schaeffer, P., Cazaubon, C., Chatelain, P. Eur. J. Pharmacol. (1993) [Pubmed]
  20. Angiotensin II-elicited signal transduction via AT1 receptors in endothelial cells. Pueyo, M.E., N'Diaye, N., Michel, J.B. Br. J. Pharmacol. (1996) [Pubmed]
  21. Expression of aldosterone synthase cytochrome P450 (P450aldo) mRNA in rat adrenal glomerulosa cells by angiotensin II type 1 receptor. Kakiki, M., Morohashi, K., Nomura, M., Omura, T., Horie, T. Endocr. Res. (1997) [Pubmed]
  22. Autoradiographic identification of brain angiotensin IV binding sites and differential c-Fos expression following intracerebroventricular injection of angiotensin II and IV in rats. Roberts, K.A., Krebs, L.T., Kramár, E.A., Shaffer, M.J., Harding, J.W., Wright, J.W. Brain Res. (1995) [Pubmed]
  23. Role of angiotensin in the extravascular system. Lees, K.R., MacFadyen, R.J., Doig, J.K., Reid, J.L. Journal of human hypertension. (1993) [Pubmed]
  24. Heterogeneity of angiotensin II AT2 receptors in the rat brain. Tsutsumi, K., Saavedra, J.M. Mol. Pharmacol. (1992) [Pubmed]
  25. Characterization of the binding properties and physiological action of divalinal-angiotensin IV, a putative AT4 receptor antagonist. Krebs, L.T., Kramár, E.A., Hanesworth, J.M., Sardinia, M.F., Ball, A.E., Wright, J.W., Harding, J.W. Regul. Pept. (1996) [Pubmed]
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