Design, Synthesis, and Biological Evaluation of the First Selective Nonpeptide AT2 Receptor Agonist
2004 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 47, no 24, 5995-6008 p.Article in journal (Refereed) Published
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.
Place, publisher, year, edition, pages
2004. Vol. 47, no 24, 5995-6008 p.
Administration; Oral, Animals, Antihypertensive Agents/chemical synthesis/chemistry/pharmacology, Bicarbonates/metabolism, Biological Availability, Cell Line, Drug Design, Enzyme Activation, Female, Half-Life, In Vitro, Intestinal Mucosa/metabolism, Liver/metabolism, Male, Mitogen-Activated Protein Kinases/metabolism, Molecular Mimicry, Neurites/drug effects/physiology, Peptides/chemistry, Radioligand Assay, Rats, Rats; Inbred SHR, Rats; Sprague-Dawley, Receptor; Angiotensin; Type 2/*agonists/metabolism, Research Support; Non-U.S. Gov't, Sulfonamides/*chemical synthesis/chemistry/pharmacology, Swine, Thiophenes/*chemical synthesis/chemistry/pharmacology, Uterus/metabolism
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-97463DOI: 10.1021/jm049715tPubMedID: 15537354OAI: oai:DiVA.org:uu-97463DiVA: diva2:172423