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

• DOI: 10.1021/jm049715t
• Publication Date: 2004-11-11T06:40:32Z
• Authors: Yiqian Wan; Charlotta Wallinder; Bianca Plouffe; Hélène Beaudry; A. K. Mahalingam; Xiongyu Wu; Berndt Johansson; Mathias Holm; Milad Botoros; Anders Karlén; Anders Pettersson; Fred Nyberg; Lars Fändriks; Nicole Gallo-Payet; Anders Hallberg; Mathias Alterman
• Keywords: Male; 0301 basic medicine; Molecular Mimicry; Administration, Oral; Biological Availability; In Vitro Techniques; Cell Line; Rats; Enzyme Activation; Bicarbonates; Radioligand Assay; 03 medical and health sciences; Liver; Drug Design; Neurites; Animals; Female; Intestinal Mucosa; Mitogen-Activated Protein Kinases; Peptides; Antihypertensive Agents; Half-Life

The first druglike selective angiotensin II AT(2) receptor agonist (21) 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 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 AT(2) receptor. Compound 21, derived from the prototype nonselective AT(1)/AT(2) receptor agonist L-162,313 will serve as a valuable research tool, enabling studies of the function of the AT(2) receptor in more detail.