Design, synthesis, and biological evaluation of the first selective nonpeptide AT2 receptor agonist.
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.
Wan
Yiqian
Y
Department of Medicinal Chemistry, BMC, Uppsala University, P.O. Box 574, SE-751 23 Uppsala, Sweden.
Wallinder
Charlotta
C
Plouffe
Bianca
B
Beaudry
Hélène
H
Mahalingam
A K
AK
Wu
Xiongyu
X
Johansson
Berndt
B
Holm
Mathias
M
Botoros
Milad
M
Karlén
Anders
A
Pettersson
Anders
A
Nyberg
Fred
F
Fändriks
Lars
L
Gallo-Payet
Nicole
N
Hallberg
Anders
A
Alterman
Mathias
M
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
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