Discovery of a Novel Non-Peptide Somatostatin Agonist with SST₄ Selectivity

Abstract

The discovery of novel non-peptide compounds with a high affinity for the peptide hormone somatostatin (SST) receptor is described. The compounds were tested for affinity at five human SST receptor subtypes individually expressed in mammalian cells. The compound NNC 26-9100 showed a K i of 6 nM at SST 4 and more than 100 fold selectivity for SST 4 over SST 1, SST 2, SST 3, or SST 5 . Competition binding studies and Scatchard analysis of the interaction by NNC 26-9100 with SST showed specificity at SST 4 . Furthermore, NNC 26-9100 was highly selective for SST 4 over a variety of other G protein-coupled receptors, having affinities for M 1 muscarinic acetylcholin and D 3 dopamine receptors of around 500 and 1000 nM, respectively. Finally, NNC 26-9100 was found to fully inhibit forskolin-induced accumulation of adenosine 3‘,5‘-cyclic monophosphate in baby hamster kidney cells, expressing the human SST 4 receptor with an EC 50 of 2 nM.