A potent cyclic hexapeptide analogue of somatostatin

Abstract

Conformational analysis has resulted in the design and synthesis of somatostatin analogues which show increased duration of action^1–3. The introduction of covalent conformational constraints and elimination of amino acids that are not required led to the synthesis of the highly active bicyclic analogue I, cyclo(Aha-Cys-Phe-D-Trp-Lys-Thr-Cys)^2,3, which showed potency equal to or greater than that of somatostatin for the inhibition of growth hormone release in vitro and in vivo, as well as for the inhibition of glucagon and insulin release in vivo (Aha, 7-aminoheptanoic acid). These results suggested that the amino acids -Phe-D-Trp-Lys-Thr- of this analogue and the corresponding residues 7–10 of somatostatin contain all the elements necessary for the expression of the above biological activities, and that the fragment -Cys-Aha-Ctys- serves as a conformational constraint, allowing the tetrapeptide to attain a bioactive conformation. It was concluded that such constraint also results in the observed reduced susceptibility to metabolism by peptidases such as trypsin and has permitted both a long duration of action and oral activity^2,3. If the sole purpose of the -Cys-Aha-Cys- sequence is indeed only conformational constraint, then it should be possible to design alternative, simpler constraining moieties. We have used a computer modelling and graphics system⁴ to examine possible alternative molecular fragments and report here the synthesis of a highly active cyclic hexapeptide analogue of somatostatin.