Abstract
Structural alterations in the 2- and 5-positions of the first drug-like selective angiotensin II AT2 receptor agonist (1) have been performed. The imidazole ring system was proven to be a strong determinant for the AT2 selectivity, and with few exceptions all variations gave good AT2 receptor affinities and with retained high AT2/AT1 selectivities. On the contrary to the findings with AT1 receptor agonists, the impact of structural modifications in the 5-position of the AT2 selective compounds were less pronounced regarding activation of the AT2 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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Benzimidazoles / chemical synthesis*
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Benzimidazoles / chemistry
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Benzimidazoles / pharmacology
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Cell Differentiation / drug effects
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Cell Line, Tumor
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Female
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Ligands
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Liver / metabolism
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Neurites / drug effects
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Neurites / physiology
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Radioligand Assay
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Rats
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Receptor, Angiotensin, Type 2 / agonists*
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Structure-Activity Relationship
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Sulfonamides / chemical synthesis*
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Sulfonamides / chemistry
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Sulfonamides / pharmacology
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Swine
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Thiophenes / chemical synthesis*
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Thiophenes / chemistry
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Thiophenes / pharmacology
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Uterus / metabolism
Substances
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Benzimidazoles
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Ligands
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N-butyloxycarbonyl-2-(4-imidazol-1-ylmethylphenyl)-4-butoxybenzenesulfonamide
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N-butyloxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-propylthiophene-2-sulfonamide
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Receptor, Angiotensin, Type 2
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Sulfonamides
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Thiophenes