Selective angiotensin II AT ₂ receptor agonists: Arylbenzylimidazole structure-activity relationships

Structural alterations in the 2- and 5-positions of the first drug-like selective angiotensin II AT ₂ receptor agonist (1) have been performed. The imidazole ring system was proven to be a strong determinant for the AT ₂ selectivity, and with few exceptions all variations gave good AT ₂ receptor affinities and with retained high AT ₂ /AT ₁ selectivities. On the contrary to the findings with AT ₁ receptor agonists, the impact of structural modifications in the 5-position of the AT ₂ selective compounds were less pronounced regarding activation of the AT ₂ receptor. The butyloxyphenyl (56) and the propylthienyl (50) derivatives were found to exert a high agonistic effect as deduced from their capacity to induce neurite elongation in neuronal cells, as does angiotensin II.