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.
Subject(s)
Angiotensin II Type 2 Receptor Blockers/chemical synthesis , Carbamates/chemical synthesis , Imidazoles/chemical synthesis , Receptor, Angiotensin, Type 2/metabolism , Sulfonamides/chemical synthesis , Thiophenes/chemical synthesis , Angiotensin II Type 2 Receptor Blockers/chemistry , Angiotensin II Type 2 Receptor Blockers/pharmacology , Animals , Carbamates/chemistry , Carbamates/pharmacology , Female , Imidazoles/chemistry , Imidazoles/pharmacology , In Vitro Techniques , Liver/metabolism , Myometrium/metabolism , Radioligand Assay , Rats , Receptor, Angiotensin, Type 2/agonists , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/pharmacology , Swine , Thiophenes/chemistry , Thiophenes/pharmacologyABSTRACT
Structural alterations to the benzylic position of the first drug-like selective angiotensin II AT(2) receptor agonist (1) have been performed, with the emphasis to reduce the CYP 450 inhibitory property of the initial structure. The imidazole moiety, responsible for the CYP 450 inhibitory effect in 1, was replaced with various heterocycles. In addition, the modes of attachment of the heterocycles, that is, carbon versus nitrogen attachment, and introduction of carbonyl functionalities to the benzylic position have been evaluated. In all the three series, AT(2) receptor ligands with affinity in the lower nanomolar range were identified. None of the analogues, regardless of the substituents, exhibited any affinity for the AT(1) receptor. Compounds with substantially reduced inhibition of the CYP 450 enzymes were obtained. Among them the compound 60 was found to induce neurite elongation in NG 108-15 cells and served as potent AT(2) selective agonist.
Subject(s)
Cytochrome P-450 Enzyme Inhibitors , Receptor, Angiotensin, Type 2/agonists , Sulfonamides/chemistry , Thiophenes/chemistry , Animals , Cytochrome P-450 Enzyme System/metabolism , Heterocyclic Compounds/chemical synthesis , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacology , Hybrid Cells , Imidazoles/chemistry , Mice , Neurites/metabolism , Protein Binding , Rats , Receptor, Angiotensin, Type 2/metabolism , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/pharmacology , Thiophenes/chemical synthesis , Thiophenes/pharmacologyABSTRACT
A versatile parallel synthetic method to obtain three series of non-cyclic analogues of the first drug-like selective angiotensin II AT(2) receptor agonist (1) has been developed. In analogy with the transformation of losartan to valsartan it was demonstrated that a non-cyclic moiety could be employed as an imidazole replacement to obtain AT(2) selective compounds. In all the three series, AT(2) receptor ligands with affinities in the lower nanomolar range were found. None of the analogues exhibited any affinity for the AT(1) receptor. Four compounds, 17, 22, 39 and 51, were examined in a neurite outgrowth cell assay. All four compounds were found to exert a high agonistic effect as deduced from their capacity to induce neurite elongation in neuronal cells, as does angiotensin II.
Subject(s)
Imidazoles/pharmacology , Receptor, Angiotensin, Type 2/agonists , Animals , Binding Sites , Cell Differentiation/drug effects , Cell Line, Tumor , Cell Membrane/chemistry , Female , Humans , Imidazoles/chemical synthesis , Imidazoles/chemistry , In Vitro Techniques , Ligands , Molecular Structure , Myometrium/chemistry , Stereoisomerism , Structure-Activity Relationship , SwineABSTRACT
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.
