N-Acyl-β2/β3-dipeptide-amide somatostatin analogs, 5 – 8, with β2-HTrp-β3-HLys ('natural' sequence) and β2-HLys-β3-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-Ac-tetrapeptide 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.
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Seebàch et al. (2001) studied this question.