Compound 22 is the first drug-like selective non-peptide AT2 receptor agonist, demonstrating oral bioavailability and biological activity similar to endogenous angiotensin II, serving as a valuable research tool.
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No clinical translation yet; leaves open whether selective non-peptide AT2 agonism offers antihypertensive benefit in humans.
The development of the first drug-like selective angiotensin II type 2 (AT(2)) receptor agonist (22) derived from the non-selective angiotensin II type 1 (AT( 1)) receptor/AT(2) receptor agonist L-162,313 is presented. Compound 22 with a K(i) value of 0.4 nM for the AT( 2) receptor and a K(i) > 10 microM for the AT(1) receptor induces outgrowth of neurite cells, stimulates p42/p44( mapk), enhances in vivo duodenal alkaline secretion in Sprague-Dawley rats and lowers the mean arterial blood pressure in anaesthetised spontaneously hypertensive rats. Thus, the peptidomimetic 22 exerts a similar biological response as the endogenous peptide angiotensin II after selective activation of the AT(2) receptor. In addition, Compound 22 has a bioavailability of 20-30% after oral administration and a half-life estimated to four hours in the rat. Compound 22 will therefore serve as a valuable research tool enabling studies of the function of the AT(2) receptor in more detail.
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Mathias Alterman (2009) studied this question.
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