Abstract
The angiotensin II (Ang II) type 1 and type 2 receptors (AT1R and AT2R) orchestrate an array of biological processes that regulate human health. Aberrant function of these receptors triggers pathophysiological responses that can ultimately lead to death. Therefore, it is important to design and synthesize compounds that affect beneficially these two receptors. Cardiovascular disease, which is attributed to the overactivation of the vasoactive peptide hormone Αng II, can now be treated with commercial AT1R antagonists. Herein, recent achievements in rational drug design and synthesis of molecules acting on the two AT receptors are reviewed. Quantitative structure activity relationships (QSAR) and molecular modeling on the two receptors aim to assist the search for new active compounds. As AT1R and AT2R are GPCRs and drug action is localized in the transmembrane region the role of membrane bilayers is exploited. The future perspectives in this field are outlined. Tremendous progress in the field is expected if the two receptors are crystallized, as this will assist the structure based screening of the chemical space and lead to new potent therapeutic agents in cardiovascular and other diseases.
Highlights
The renin angiotensin system (RAS) is the main target for regulating the body’s blood pressure [1].This is a bioenzymatic system where angiotensinogen, through the two enzymes renin and angiotensin converting enzyme (ACE), is converted to the octapeptide hormone angiotensin II (Ang II) that in pathological conditions causes vasoconstriction
We have gained more knowledge on RAS: First, we know that more biochemical pathways are affecting the conversion of angiotensinogen to Ang II; second, Ang II affects mainly two GPCR receptor subtypes, namely AT1R and AT2R, at least four different subtypes have been identified
The action of Ang II on AT1R was the first to be studied in detail, while the mode of action of AT2R remained elusive for a long time owing to the lack of ligands that selectively target this receptor as due to its low expression [8,9,10,11]
Summary
The renin angiotensin system (RAS) is the main target for regulating the body’s blood pressure [1]. Rein et al [38,39] reported that mice lacking AT2R exhibited a higher BP and higher sensitivity to an angiotensin II-induced hypertensive effect than normal mice This information triggered the effort towards the discovery of AT2R agonists as antihypertensive targets. This review article focuses on recent efforts on the design and synthesis of small bioactive molecules that can act on AT1R and AT2R. In addition to the synthetic efforts in the recent years, parallel attempts have been made to model the two receptors using new approaches Without doubt, these approaches can aid the design and synthesis of new molecules acting on the two receptors. These approaches can aid the design and synthesis of new molecules acting on the two receptors Our hope is that this article will assist medicinal chemists to design, synthesize and discover new drugs possessing beneficial effects for major diseases such as cardiovascular and cancer
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