Development of selective non-peptide angiotensin II type 2 receptor agonists.
The development of the first drug-like selective angiotensin II type 2 (AT(2)) receptor agonist (22) derived from the non-selective angiotensin II type 1 (AT( 1)) receptor/AT(2) receptor agonist L-162,313 is presented. Compound 22 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 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 anaesthetised spontaneously hypertensive rats. Thus, the peptidomimetic 22 exerts a similar biological response as the endogenous peptide angiotensin II after selective activation of the AT(2) receptor. In addition, Compound 22 has a bioavailability of 20-30% after oral administration and a half-life estimated to four hours in the rat. Compound 22 will therefore serve as a valuable research tool enabling studies of the function of the AT(2) receptor in more detail.
Alterman
Mathias
M
Department of Medicinal Chemistry, BMC, Uppsala University, Uppsala, Sweden. mathias.alterman@orgfarm.uu.se
D047228:Angiotensin II Type 1 Receptor Blockers / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001713:Biphenyl Compounds / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D016501:Neurites / Q000187:drug effects / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044139:Receptor, Angiotensin, Type 2 / Q000819:agonists*; D013449:Sulfonamides / Q000378:metabolism
D047228:Angiotensin II Type 1 Receptor Blockers; D001713:Biphenyl Compounds; D007093:Imidazoles; C091630:L 162313; D010455:Peptides; D044139:Receptor, Angiotensin, Type 2; D013449:Sulfonamides; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3