Linear, peptidase-resistant β ²/β ³-Di- and α/β ³-tetrapeptide derivatives with nanomolar affinities to a human somatostatin receptor

N-Acyl-β ³/β ³-dipeptide-amide somatostatin analogs, 5-8, with β ²-HTrp-β ³-HLys ('natural' sequence) and β ²-HLys-β ³-HTrp (retro-sequence) have been synthesized (in solution). Depending on their relative configurations and on the nature of the terminal N-acyl and terminal C-amino group, the linear β-dipeptide derivatives have affinities for the human receptor hsst 4, ranging from 250 to > 10000 nanomolar (Fig. 3). Also, N-Actetrapeptide amides 9 and 10, which contain one α- and three β-amino acid residues (N-β-α-β-β-C), have been prepared (solid-phase synthesis), with the natural (Phe, Trp, Lys, Thr) and the retro-sequence (Thr, Lys, Trp, Phe) of side chains and with two different configurations, each, of the two central amino acid residues. The novel 'mixed', linear α/β-peptides have affinities for the hsst 4 receptor ranging from 23 to > 10000 nanomolar (Fig. 4), and, like 'pure' β-peptides, they are completely stable to a series of proteolytic enzymes. Thus, the peptidic turn of the cyclic tetradecapeptide somatostatin (Fig. 1) can be mimicked by simple linear di- and tetrapeptides. The tendency of β-dipeptides for forming hydrogen-bonded rings is confirmed by calculations at the B3LYP/6-31G(d,p) level (Fig. 2). The reported results open new avenues for the design of low-molecular-weight peptidic drugs.