Design, Synthesis, and Biological Evaluation of the First Selective Nonpeptide AT2 Receptor Agonist

The first druglike selective angiotensin II AT2 receptor agonist (21) with a Ki value of 0.4 nM for the AT2 receptor and a Ki >10 μM for the AT1 receptor is reported. Compound 21, with a bioavailability of 20−30% after oral administration and a half-life estimated to 4 h in rat, induces outgrowth of neurite cells, stimulates p42/p44mapk, enhances in vivo duodenal alkaline secretion in Sprague−Dawley rats, and lowers the mean arterial blood pressure in anesthetized, spontaneously hypertensive rats. Thus, the peptidomimetic 21 exerts a similar biological response as the endogenous peptide angiotensin II after selective activation of the AT2 receptor. Compound 21, derived from the prototype nonselective AT1/AT2 receptor agonist L-162,313 will serve as a valuable research tool, enabling studies of the function of the AT2 receptor in more detail.