RESUMO
Non-peptidic compounds containing the octahydro-indolo[4,3-fg]quinoline (ergoline) structural element have been optimized into derivatives with high affinity (pK(d) r sst(1)>9) and selectivity (>1000-fold for h sst(1) over h sst(2)-h sst(5)) for the somatostatin sst(1) receptor. In functional assays, these ergolines act as antagonists at human recombinant sst(1) receptors. Pharmacokinetic studies in rodents reveal good oral bioavailability and brain penetration for some of these compounds.
Assuntos
Ergolinas , Receptores de Somatostatina/antagonistas & inibidores , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Ergolinas/síntese química , Ergolinas/química , Ergolinas/farmacocinética , Ergolinas/farmacologia , Humanos , Estrutura Molecular , Ratos , Somatostatina/fisiologiaRESUMO
The SAR of over 50 derivatives of octahydrobenzo[g]quinoline (obeline)-type somatostatin sst(1) receptor antagonist 1 is presented, focusing on the modification of its arylpiperazine moiety. Sst(1) affinities in this series cover a range of five orders of magnitude with the best derivatives displaying subnanomolar sst(1) affinities and >10,000-fold selectivities over the sst(2) receptor subtype as well as promising pharmacokinetic properties.
Assuntos
Proteínas Luminescentes/farmacologia , Piperazinas/farmacologia , Receptores de Somatostatina/antagonistas & inibidores , Proteínas Luminescentes/química , Piperazinas/química , Relação Estrutura-AtividadeRESUMO
A novel class of non-peptide somatostatin receptor ligands bearing the octahydrobenzo[g]quinoline (obeline) structural element has been identified. SAR studies have been performed that led to the discovery of derivatives with high affinity (pK(d) r sst(1) > or = 9) and selectivity (> or = 150-fold for h sst(1) over h sst(2)-h sst(5)) for somatostatin receptor subtype sst(1). In a functional assay, the compounds act as antagonists at human recombinant sst(1) receptors.