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

Abstract

The first druglike selective angiotensin II AT₂ receptor agonist (21) with a K_i value of 0.4 nM for the AT₂ receptor and a K_i >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/p44^mapk, 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.