title: Comparative functional properties of two structurally similar selective nonpeptide drug-like ligands for the angiotensin II type-2 (AT(2)) receptor. Effects on neurite outgrowth in NG108-15 cells.
abstract: There is increasing evidence that angiotensin II (Ang II), through binding to the type 2 (AT(2)) receptor may have beneficial effects in various physiological and pathological situations. However, specific action presumably mediated by the angiotensin AT(2) receptor has been hampered by the absence of appropriate selective ligands. The aim of this study was to compare the biological properties of two related and selective drug-like nonpeptide AT(2) ligands, namely an agonist called M024 (also known as Compound 21) and a new ligand, presumably an antagonist, C38/M132, (originally called C38). Properties of the compounds were investigated in NG108-15 cells expressing angiotensin AT(2) receptor and known to develop neurite outgrowth upon Ang II stimulation. NG108-15 cells stimulated for three days with C21/M024 (0.1 or 100nM) exhibited the same neurite outgrowth as cells stimulated with Ang II (100nM) while co-incubation of Ang II or C21/M024 with C38/M132 (10 or 100nM) inhibited their effects, similarly to the angiotensin AT(2) receptor antagonist, PD123319 (10μM). As Ang II, C21/M024 induced a Rap1-dependent activation of p42/p44(mapk) whereas preincubation of cells with C38/M132 inhibited p42/p44(mapk) and Rap1 activation induced by Ang II. Three-day treatment with C21/M024 or Ang II decreased cell number in culture, an effect that was rescued by preincubation with C38/M132. Taken together, these results indicate that the nonpeptide ligand C21/M024 is a potent angiotensin AT(2) receptor agonist while C38/M132 acts as an antagonist. These selective nonpeptide angiotensin AT(2) ligands may represent unique and long-awaited tools for the pursuit of in vivo studies.
authors.affiliation: Service of Endocrinology and Department of Physiology and Biophysics, Faculty of Medicine, Université de Sherbrooke, Sherbrooke, QC, Canada J1H 5N4.
authors.forename: Marie-Odile
authors.initials: MO
authors.lastname: Guimond
authors.forename: Charlotta
authors.initials: C
authors.lastname: Wallinder
authors.forename: Mathias
authors.initials: M
authors.lastname: Alterman
authors.forename: Anders
authors.initials: A
authors.lastname: Hallberg
authors.forename: Nicole
authors.initials: N
authors.lastname: Gallo-Payet
mesh_terms: D000804:Angiotensin II / Q000008:administration & dosage / Q000378:metabolism; D057912:Angiotensin II Type 2 Receptor Blockers / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D002219:Carbamates / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology*; D008024:Ligands; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D016501:Neurites / Q000187:drug effects* / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D044139:Receptor, Angiotensin, Type 2 / Q000819:agonists / Q000187:drug effects* / Q000378:metabolism; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology*; D045162:Thiazolidinediones / Q000494:pharmacology*; D013876:Thiophenes / Q000008:administration & dosage / Q000494:pharmacology*; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism
chemical_list: C583158:3-(3-imidazol-1-ylmethylphenyl)-5-isobutylthiophene-2-(N-butyloxycarbonyl)sulfonamide; C583084:5-((5-bromo-1H-indol-3-yl)methylene)-3-(4-chlorobenzyl)thiazolidine-2,4-dione; D057912:Angiotensin II Type 2 Receptor Blockers; D002219:Carbamates; D007093:Imidazoles; D007211:Indoles; D008024:Ligands; C494557:N-butyloxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-isobutylthiophene-2-sulfonamide; D011725:Pyridines; D044139:Receptor, Angiotensin, Type 2; D013449:Sulfonamides; D045162:Thiazolidinediones; D013876:Thiophenes; D000804:Angiotensin II; C073402:PD 123319; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020827:rap1 GTP-Binding Proteins