Ergoline derivatives as highly potent and selective antagonists at the somatostatin sst1 receptor

Non-peptidic compounds containing the octahydro-indolo[4,3-fg]quinoline (ergoline) structural element have been optimized into derivatives with high affinity (pKd r sst1 > 9) and selectivity (>1000-fold for h sst1 over h sst2–h sst5) for the somatostatin sst1 receptor. In functional assays, these ergolines act as antagonists at human recombinant sst1 receptors. Pharmacokinetic studies in rodents reveal good oral bioavailability and brain penetration for some of these compounds.

The optimization of ergoline derivatives into highly potent and selective non-peptidic somatostatin sst1 receptor ligands is described. Derivatives 19 and 30 show sub-nanomolar affinity to the sst1 receptor and >1000-fold selectivity over other somatostatin receptor subtypes. They behave as full antagonists in functional assays and show promising PK properties in rodents.Figure optionsDownload as PowerPoint slide