New open-chain and cyclic tetrapeptides, consisting of alpha-, beta(2)-, and beta(3)-amino-acid residues, as somatostatin mimics - A survey

Cyclo-beta-tetrapeptides are known to adopt a conformation with an intramolecular transannular hydrogen bond in solution. Analysis of this structure reveals that incorporation of a beta(2)-amino-acid residue should lead to mimics of 'alpha-peptidic beta-turns' (cf A, B, C). It is also known that short-chain mixed beta/alpha-peptides with appropriate side chains can be used to mimic interactions between alpha-peptidic hairpin turns and G protein-coupled receptors. Based on these facts, we have now prepared a number of cyclic and open-chain tetrapeptides, 7-20, consisting of alpha-, beta(2)-, and beta(3)-amino-acid residues, which bear the side chains of Trp and Lys, and possess backbone configurations such that they should be capable of mimicking somatostatin in its affinity for the human SRIF receptors (hsst(1-5)). All peptides were prepared by solid-phase coupling by the Fmoc strategy. For the cyclic peptides, the three-dimensional orthogonal methodology (Scheme 3) was employed with best success. The new compounds were characterized by high-resolution mass spectrometry, NMR and CD spectroscopy, and, in five cases, by a full NMR-solution-structure determination (in MeOH or H2O Fig. 4). The affinities of the new compounds for the receptors hsst(1-5) were determined by competition with [(125)]LTT-SRIF28 or [(125)] [Tyr(10)]-CST14. In Table 1, the data are listed, together with corresponding values of all beta- and gamma-peptidic somatostatin/Sandostatin (R) mimics measured previously by our groups. Submicromolar affinities have been achieved for most of the human SRIF receptors hsst(1-5). Especially high, specific binding affinities for receptor hSSt(4) (which is highly expressed in lung and brain tissue, although still of unknown function!) was observed with some of the beta-peptidic mimics. In view of the fact that numerous peptide-activated G protein-coupled receptors (GPCRs) recognize ligands with turn structure (Table 2), the results reported herein are relevant far beyond the realm of somatostatin: many other peptide GPCRs should be 'reached' with beta- and gamma-peptidic mimics as well, and these compounds are proteolytically and metabolically stable, and do not need to be cell-penetrating for this purpose (Fig. 5).