title: Design, synthesis, and biological evaluation of the first selective nonpeptide AT2 receptor agonist.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, BMC, Uppsala University, P.O. Box 574, SE-751 23 Uppsala, Sweden.
authors.forename: Yiqian
authors.initials: Y
authors.lastname: Wan
authors.forename: Charlotta
authors.initials: C
authors.lastname: Wallinder
authors.forename: Bianca
authors.initials: B
authors.lastname: Plouffe
authors.forename: Hélène
authors.initials: H
authors.lastname: Beaudry
authors.forename: A K
authors.initials: AK
authors.lastname: Mahalingam
authors.forename: Xiongyu
authors.initials: X
authors.lastname: Wu
authors.forename: Berndt
authors.initials: B
authors.lastname: Johansson
authors.forename: Mathias
authors.initials: M
authors.lastname: Holm
authors.forename: Milad
authors.initials: M
authors.lastname: Botoros
authors.forename: Anders
authors.initials: A
authors.lastname: Karlén
authors.forename: Anders
authors.initials: A
authors.lastname: Pettersson
authors.forename: Fred
authors.initials: F
authors.lastname: Nyberg
authors.forename: Lars
authors.initials: L
authors.lastname: Fändriks
authors.forename: Nicole
authors.initials: N
authors.lastname: Gallo-Payet
authors.forename: Anders
authors.initials: A
authors.lastname: Hallberg
authors.forename: Mathias
authors.initials: M
authors.lastname: Alterman
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001639:Bicarbonates / Q000378:metabolism; D001682:Biological Availability; D002460:Cell Line; D015195:Drug Design; D004789:Enzyme Activation; D005260:Female; D006207:Half-Life; D066298:In Vitro Techniques; D007413:Intestinal Mucosa / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D018716:Molecular Mimicry; D016501:Neurites / Q000187:drug effects / Q000502:physiology; D010455:Peptides / Q000737:chemistry; D011869:Radioligand Assay; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D044139:Receptor, Angiotensin, Type 2 / Q000819:agonists* / Q000378:metabolism; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013552:Swine; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014599:Uterus / Q000378:metabolism
chemical_list: D000959:Antihypertensive Agents; D001639:Bicarbonates; C494557:N-butyloxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-isobutylthiophene-2-sulfonamide; D010455:Peptides; D044139:Receptor, Angiotensin, Type 2; D013449:Sulfonamides; D013876:Thiophenes; D020928:Mitogen-Activated Protein Kinases