DESIGN, COMPUTER DERIVED STRUCTURE AND BIOLOGICAL ACTIVITY OF THREE BICYCLIC GONADOTROPIN RELEASING HORMONE (GnRH) ANTAGONISTS

In order to determine the bioactive conformation of GnRH we decided to synthesize fully rigid and biologically active analogs which could be studied ultimately by NMR spectroscopy or X-ray crystallography. Because we had found that bridging GnRH sequences at positions 1 and 10 or 4 and 10 in fact lead to partial agonists and antagonists resp., and because we have more latitude in the selection of amino acid substitutions in the design of antagonists, we designed, synthesized and tested cyclic GnRH antagonists. These antagonists are characterized by specific substitutions at positions 1, 2 and 3. Here, we show that some antagonists of GnRH which had been bridged at positions 4 and 10 and had been found to be equipotent to the most potent linear analogs, could be further constrained by the introduction of a second bridge between residues 5 and 8 with retention of high potency.