New Low Histamine Release Side Effects Of Luteinizing Hormone Releasing Hormone (lhrh) Long-acting Antagonist Design

According to the reported research of LHRH antagonists with histamine-releasing potency, and the structure property of histamine-releasing peptides which contain one or more basic amino acids, it was hypothesized that introduction of the acid 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.LHRH antagonist, LXT-300, was selected as model peptide. The designed groups with different acidity and basicity were introduced at positions 6 and 8.21 new deca-peptides was designed and synthesized. Bioactivities of these compounds were evaluated using a testosterone level test model in rats, 9 of analogues inhibited testosterone secretion for 24h, and were longer than LXT-300(about 8h); Histamine-releasing effects of 17 new LHRH antagonists were tested with rat peritoneal mass cells in vitro, and 5 of them showed longer duration of inhibiting testosterone secretion and lower histamine releasing activity than LXT-300 in the test. The experiment results as follows:1. LHRH analogues with basic, neutral or acidic amino acid at position 6 showed the bio-activity of inhibiting testosterone secretion. The bio-activity of inhibiting testosterone secretion were reduced for the analogues with neutral and acidic groups at position 8.2. Keeping the alkalinity at position 8, D-Glu~6 analogue had lower histamine releasing activity than analogues of D-Pro,D-Asn or D-Amp at position 6; Reducing the alkalinity and increasing the flexility of the side chain at position 6 could reduce the histamine-releasing effect of LHRH analogues; And also the histamine-releasing effect could be obviously reduced with the neutral or acidic groups at position 8, but they were no bio-activity. Reducing the alkalinity at position 8 was useful to gain the LHRH analogues with long bio-activity and low histamine-releasing effect.The results seemed to favor previous 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.