[Synthesis and analysis of potent cyclic analogs of the ACTH active center]

Linear and cyclic analogues of the specific active center of the ACTH molecule have been synthesized, viz. [Lis5]ACTH-(5-10)-, [Lys5, cyclo (Gly10----epsilon Lys5)]-ACTH-(5-10)-hexapeptides, [Lys5 (Gly)]ACTH-(5-10)- and [Lys5, Gly11, cyclo (Gly11----epsilon Lys5)]-ACTH-(5-11)-heptapeptides. The cyclic structures are fixed by covalent bond between the COOH-group of the C-terminal glycine and epsilon-amino group of a lysine residue. Azide method, DCC/HOBT or pentafluorophenyl esters are used for fragment coupling, while cyclization is achieved by means of diphenylphosphoryl azide or pentafluorophenyl esters. Cyclic compounds are 2-3 orders of magnitude more active than their linear counterparts as revealed by assaying their melanocyte-stimulating activity in vitro on frog skin. Only the title heptapeptide possesses a steroidogenic activity similar to that of ACTH-(5-10)-hexapeptide. The results obtained are in accord with the idea implying the formation in the hormone-receptor complexes of quasi-cyclic structures in the region of the specific active center of ACTH molecule.