title: From the first selective non-peptide AT(2) receptor agonist to structurally related antagonists.
abstract: A para substitution pattern of the phenyl ring is a characteristic feature of the first reported selective AT(2) receptor agonist M024/C21 (1) and all the nonpeptidic AT(2) receptor agonists described so far. Two series of compounds structurally related to 1 but with a meta substitution pattern have now been synthesized and biologically evaluated for their affinity to the AT(1) and AT(2) receptors. A high AT(2)/AT(1) receptor selectivity was obtained with all 41 compounds synthesized, and the majority exhibited K(i) ranging from 2 to 100 nM. Five compounds were evaluated for their functional activity at the AT(2) receptor, applying a neurite outgrowth assay in NG108-15 cells. Notably, four of the five compounds, with representatives from both series, acted as potent AT(2) receptor antagonists. These compounds were found to be considerably more effective than PD 123,319, the standard AT(2) receptor antagonist used in most laboratories. No AT(2) receptor antagonists were previously reported among the derivatives with a para substitution pattern. Hence, by a minor modification of the agonist 1 it could be transformed into the antagonist, compound 38. These compounds should serve as valuable tools in the assessment of the role of the AT(2) receptor in more complex physiological models.
authors.affiliation: Department of Medicinal Chemistry, BMC, Uppsala University, P.O. Box 574, SE-751 23 Uppsala, Sweden.
authors.forename: A M S
authors.initials: AM
authors.lastname: Murugaiah
authors.forename: Xiongyu
authors.initials: X
authors.lastname: Wu
authors.forename: Charlotta
authors.initials: C
authors.lastname: Wallinder
authors.forename: A K
authors.initials: AK
authors.lastname: Mahalingam
authors.forename: Yiqian
authors.initials: Y
authors.lastname: Wan
authors.forename: Christian
authors.initials: C
authors.lastname: Sköld
authors.forename: Milad
authors.initials: M
authors.lastname: Botros
authors.forename: Marie-Odile
authors.initials: MO
authors.lastname: Guimond
authors.forename: Advait
authors.initials: A
authors.lastname: Joshi
authors.forename: Fred
authors.initials: F
authors.lastname: Nyberg
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: D057912:Angiotensin II Type 2 Receptor Blockers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D002219:Carbamates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism; D009215:Myometrium / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D044139:Receptor, Angiotensin, Type 2 / Q000819:agonists / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013552:Swine; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C583158:3-(3-imidazol-1-ylmethylphenyl)-5-isobutylthiophene-2-(N-butyloxycarbonyl)sulfonamide; D057912:Angiotensin II Type 2 Receptor Blockers; D002219:Carbamates; D007093:Imidazoles; D044139:Receptor, Angiotensin, Type 2; D013449:Sulfonamides; D013876:Thiophenes