O Angiotensin Antagonists

There are four different subtypes of angiotensin II receptor subclasses identified to date and include AT1, AT2, AT3, and AT4. These belong to the class of G-protein-coupled receptors and are responsible for the signal transduction of the hormone. Although there is some understanding of the role AT2 plays in development of a fetus or neonate, there is very little known about the role of AT2 and AT3 in the human body. However, it is the AT1 receptors that are of particular interest in managing specific cardiovascular diseases. Studies have demonstrated that stimulation of AT1 receptors by angiotensin II result in vasoconstriction, aldosterone synthesis and secretion, increased vasopressin secretion, decreased renal blood flow, renal tubular sodium reuptake, and several other physiological events.

Administration of a competitive antagonist that inhibits angiotensin II at the AT1 receptor will produce a vasodilatory effect. Because the substrate for this receptor is an octapep-tide, much of the earlier work was performed by using various peptide systems. One such agent, saralasin, is an octapep-tide that differs from angiotensin by two amino acids. This agent's use was limited because it had some partial agonistic properties. Nevertheless, it served as a lead in the development of other agents that are useful in antagonizing the an-giotensin II receptor. The most significant lead in the development of this class came from a series of imidazole-5-acetic acid derivatives that attenuated pressor response to angiotensin II in test animals. Molecular modeling revealed that the imidazole-5-acetic acid could be exploited to mimic more closely the pharmacophore of angiotensin II. The first successful agent to be developed through this method is losartan. Later, four other agents were introduced into the U.S. market. These tend to be biphenylmethyl derivatives that possess certain acidic moieties, which can interact with various positions on the receptor, much like the substrate, angiotensin II.

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