Mimicking the tetradecapeptide somatostatin through the design of novel non-peptide small molecules is needed for developing analogues with selective or universal affinity for human somatostatin receptors (hsst1–5) and improved pharmacological properties. We report the synthesis and evaluation of the binding potential of the first all-peptoid SRIF (somatotropin release-inhibiting factor) analogues. Cyclic β and mixed α/β tetra- or pentapeptoids were efficiently obtained by macrocyclisation of the corresponding linear peptoids. In vitro competition binding experiments using [125I]-somatostatin were performed on this first generation of peptoids mimicking the SRIF pharmacophore (Phe7-(D)Trp8-Lys9-Thr10). The selectivity profiles of cyclic compounds 1 to 4 were similar with higher affinity for the sst3, sst5 and sst4 receptors and lower potency on sst1 and sst2 subtypes.
