Polypeptides. Part 15. Synthesis and biological activity of α-aza-analogues of luliberin modified in positions 6 and 10

Abstract

Analogues of luliberin (luteinising hormone-releasing hormone) and 2-dehistidyl-luliberin containing α-azaglycine (–NHNHCO–) or α-aza-alanine (–NHNMeCO–) residues in either position 6 or 10 have been synthesised by classical procedures of peptide synthesis. The agonist and antagonist activities of these compounds were evaluated in androgen-sterilised constant-oestrus rats; [10-Azgly]-, [6-Azgly]-, and [6-Azala]-luliberin were marginally less active than the parent peptide. When the aza-change in position 6 was combined with an ethylamide substitution in position 10 the resulting compounds, [6-Azgly-10-de-Gly-NH₂-9-Pro-ethylamide]- and [6-Azala-10-de-Gly-NH₂-9-Pro-ethylamide]-luliberin, were twice as active as luliberin. [6-D-Ala-10-Azgly]luliberin was also twice as active as luliberin. [2-De-His-10-Azgly]-luliberin inhibited completely ovulation induced by luliberin (0.5 µg/rat) at a dose of 250 µg/rat, but 2-de-His-analogues of all the other compounds were devoid of antagonist activity in this test system.