| According to the reported research of LHRH antagonists with histamine-releasing potency , and the structure property of histamine-releasing peptides which contain a series of functional groups, and the experience of last work, it was hypothesized that introduction of the functional groups into some sensitive sites of LHRH antagonist could reduce the histamine-releasing activity of new analogues, while the activity of inhibiting-testosterone could be retained.Recent synthesized long potent LHRH antagonist was selected as model peptide. The designed compounds with different functional groups were introduced at N-end positions 5, 6 and 7. 16 new deca-peptides was designed and synthesized. Bioactivities of these peptides were evaluated using a testosterone level test model in rats, 9 of these analogues inhibited testosterone secretion for 8h, and it was equal to control Cetrorelix, and 5 were longer than Cetrorelix,for 24h; Histamine- releasing effects of those 14 new LHRH antagonists were tested with rat peritoneal mass cells in vitro, and 5 of them showed lower histamine releasing activity than Cetrorelix in the test. The experiment results as follows:1. LHRH analogues with uramino-(Cbm-) at N-end showed the bio-activity longer than analogues with CAA at N-end, respectively for 24h and 8h, but analogues with Cbm- were equal to analogues with CAA at Histamine-releasing effects.2. Analogues with Accn (n=5 or 6) at position 7 were equal to Analogues with Leu at position 7 at evaluated using a testosterone level test model in rats.3. Whether N-end and position 6, -COOH not as a good functional groups, and acetamido-(Cbm-, Asn or Glu) as a good functional groups with long bio-activity and low histamine-releasing effect.The results seemed to favor previous a moiety of hypothesis. But it would need further study about the structure-activity of the LHRH antagonists with low histamine-releasing potency and long duration of inhibiting testosterone secretion.
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