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

• Published in: Journal of medicinal chemistry 2004-11, Vol.47 (24), p.5995-6008
• Main Authors: Wan, Yiqian, Wallinder, Charlotta, Plouffe, Bianca, Beaudry, Hélène, Mahalingam, A. K, Wu, Xiongyu, Johansson, Berndt, Holm, Mathias, Botoros, Milad, Karlén, Anders, Pettersson, Anders, Nyberg, Fred, Fändriks, Lars, Gallo-Payet, Nicole, Hallberg, Anders, Alterman, Mathias
• Format: Article
• Language: English
• Subjects: Administration, Oral; Adminstration; Angiotensin; Animals; Antihypertensive agents; Antihypertensive Agents - chemical synthesis; Antihypertensive Agents - chemistry; Antihypertensive Agents - pharmacology; Antihypertensive Agents/chemical synthesis/chemistry/pharmacology; Bicarbonates - metabolism; Biological and medical sciences; Biological Availability; Cardiovascular system; Cell Line; Drug Design; Enzyme Activation; Farmaceutisk vetenskap; Female; Half-Life; In Vitro; In Vitro Techniques; Inbred SHR; Intestinal Mucosa - metabolism; Liver - metabolism; Male; MEDICAL AND HEALTH SCIENCES; Medical sciences; MEDICIN OCH HÄLSOVETENSKAP; Mitogen-Activated Protein Kinases - metabolism; Molecular Mimicry; Neurites - drug effects; Neurites - physiology; Neurites/drug effects/physiology; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Oral; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Peptides - chemistry; Pharmaceutical Sciences; Pharmacology. Drug treatments; Radioligand Assay; Rarts; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Receptor; Receptor, Angiotensin, Type 2 - agonists; Receptor, Angiotensin, Type 2 - metabolism; Sprague-Dawley; Sulfonamides - chemical synthesis; Sulfonamides - chemistry; Sulfonamides - pharmacology; Sulfonamides/chemical synthesis/chemistry/pharmacology; Swine; Thiophenes - chemical synthesis; Thiophenes - chemistry; Thiophenes - pharmacology; Thiophenes/chemical synthesis/chemistry/pharmacology; Type 2/antagonists/metabolism; Uterus - metabolism
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/jm049715t

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.