Identification and SAR of potent and selective non-peptide obeline somatostatin sst1 receptor antagonists

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 (pKd r sst1 ⩾ 9) and selectivity (⩾150-fold for h sst1 over h sst2–h sst5) for somatostatin receptor subtype sst1. In a functional assay, the compounds act as antagonists at human recombinant sst1 receptors.

Graphical abstractThe identification of a novel class of non-peptide somatostatin sst1 receptor ligands is described. Optimization of positions 6 and 9 in these obeline-type compounds leads to functional antagonists with sub-nanomolar affinities to sst1 and >10,000-fold selectivities over the sst2 receptor subtype.Figure optionsDownload full-size imageDownload as PowerPoint slide