Beta-amino acid substituted Angiotensin II peptidomimetics as AT2 receptor-selective ligands

Widdop, RE, Kirsch, J, Bosnyak, S, Unabia, S, Del Borgo, M, Perlmutter, P, Thomas, W, Aguilar, MI and Jones, ES (2010). Beta-amino acid substituted Angiotensin II peptidomimetics as AT2 receptor-selective ligands. In: High Blood Pressure Research 2010 Scientific Sessions Abstracts. Conference on High Blood Pressure Research, Washington, DC, U.S.A., (E-118-E-118). 13-16 October 2010. doi:10.1161/HYP.0b013e3181faa059

Author Widdop, RE
Kirsch, J
Bosnyak, S
Unabia, S
Del Borgo, M
Perlmutter, P
Thomas, W
Aguilar, MI
Jones, ES
Title of paper Beta-amino acid substituted Angiotensin II peptidomimetics as AT2 receptor-selective ligands
Conference name Conference on High Blood Pressure Research
Conference location Washington, DC, U.S.A.
Conference dates 13-16 October 2010
Proceedings title High Blood Pressure Research 2010 Scientific Sessions Abstracts   Check publisher's open access policy
Journal name Hypertension   Check publisher's open access policy
Place of Publication Philadelphia, PA, U.S.A.
Publisher Lippincott Williams & Wilkins
Publication Year 2010
Year available 2010
Sub-type Poster
DOI 10.1161/HYP.0b013e3181faa059
ISSN 0194-911X
Volume 56
Issue 5
Start page E-118
End page E-118
Total pages 1
Collection year 2011
Language eng
Formatted Abstract/Summary
Angiotensin II (Ang II) binds to two main receptor subtypes, the Ang II type 1 (AT1R) and type 2 (AT2R) receptors. AT2R stimulation is believed to oppose AT1R actions, mediating vasodilatation and growth inhibition, usually via a nitric oxide-dependent pathway in the vasculature. However, research into AT2R function has been hampered by the lack of selective pharmacological tools. Therefore the aim of the present study was to use the native ligand Ang II as a template and to perform individual beta-amino acid substitutions and determine AT2R versus AT1R binding selectivity. In addition, functional vascular effects (in vitro AT2R-mediated vasorelaxation and in vivo vasodepressor action) were performed. In competition binding experiments using either AT1R- or AT2R- transfected HEK293 cells, beta-tyrosine (Y)-Ang II and beta-isoleucine (I)-Ang II fully displaced iodinated Ang II from AT2R but not AT1R sites. In mouse aortic rings, beta-amino acid substitution at the Y and I residue of Ang II evoked vasorelaxation that was sensitive to blockade by the AT2R antagonist PD123319 and the NOS inhibitor L-NAME. In vivo influence of beta- Ang II peptides on blood pressure (BP) was determined in conscious male spontaneously hypertensive rats (SHR), either alone or in combination with AT1R and AT2R antagonists in a randomised treatment protocol, over several days in the same animals. When tested with a low level of AT1R blockade (0.01mg/kg IV),beta-I Ang II (15pmol/kg/min IV for 4 hours) reduced BP in conscious SHR (beta-I Ang II ± candesartan, -24±4 mmHg) to a greater extent than candesartan alone (-11±3 mmHg; n=7, P<0.05); an effect that was abolished by concomitant PD123319 infusion. However, in an identical experimental protocol, beta-Y Ang II had no influence on BP (n=10). Thus, the current study demonstrates that a single beta-amino acid substitution resulted in a compound that demonstrated both in vitro vasorelaxation and in vivo depressor activity via a characteristic AT2R-mediated signalling pathway. This approach to the design and synthesis of novel AT2R-selective peptidomimetics shows great potential to provide insight into AT2R function and may lead to the development of future AT2R-selective therapeutics for the use in cardiovascular pathologies.
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Created: Sun, 09 Jan 2011, 00:06:55 EST