Identification of potent non-peptide somatostatin antagonists with sst3 selectivity

Using a solution-phase parallel synthesis strategy, a series of non-peptide somatostatin analogues were prepared, and their binding affinities to the five human somatostatin receptor subtypes (sst 1-5 ) were determined. Imidazolyl derivatives 2 were found to bind with moderate affinity but with high selectivity to the sst 3 receptor subtype. Further modifications of these structures led to a more potent class of ligands, the tetrahydro-β-carboline derivatives 4. Among these, compounds 4k (BN81644) and 4n (BN81674) bind selectively and with high affinity to the sst 3 receptor subtype (K i = 0.64 and 0.92 nM, respectively). Furthermore, 4k and 4n reverse the inhibition of cyclic AMP accumulation induced by 1 nM somatostatin via sst 3 receptors, with IC 50 = 2.7 and 0.84 nM, respectively. The most potent compound 4n was shown to be a competitive antagonist of human sst 3 receptors by increasing the EC 50 of SRIF-14-mediated inhibition of cAMP accumulation with a K B of 2.8 nM (where K B is the concentration of antagonist that shifts the agonist dose-response 2-fold). These new derivatives are, to our knowledge, the first potent and highly selective non-peptide human sst 3 antagonists known and, as such, are useful tools for investigating the physiological role of sst 3 receptors.