Selective FSH-releasing activity of [D-Trp9]GAP1-13: comparison with gonadotropin-releasing abilities of analogs of GAP and natural LHRHs

Abstract

We had previously shown that fragments of human gonadotropin-releasing hormone associated peptide (GAP) stimulated FSH and LH release in vivo. In particular, GAP1-13 had a preferential FSH-releasing activity. To decrease enzymatic degradation, analogs of GAP1-13 with D-amino acid substitutions were synthesized. The activities were tested in ovariectomized, estrogen-progesterone primed (OEP) rats and compared with those of GAP1-13, mammalian (m), chicken II (cII), and lamprey (1) LHRH. The peptides were injected (IV) into conscious, OEP rats and blood samples were obtained via the jugular catheter. [D-Trp9 )GAP1-13 selectively stimulated FSH release at a dose of 1 microgram. Multiple injections of this analog (10 micrograms every 30 min for 5 injections) induced a marked elevation of plasma FSH values which peaked (p less than 0.001) after the third injection. By contrast, [D-Trp9]GAP1-13 had no effect on LH and prolactin (PRL) release after either single or multiple injections. These doses of [D-Ala4]GAP1-13 had no effect on the release of FSH, LH or PRL. Both human GAP1-13 and its [D-Trp9] analog exerted a selective FSH-releasing effect at a dose of 10 micrograms, however, the [D-Trp9] analog was more potent than GAP1-13 on FSH release. The potency of [D-Trp9]GAP1-13 in releasing FSH was approximately 1/100th that of mLHRH. Chicken II LHRH had slightly selective FSH-releasing activity with a potency 1/10th that of mLHRH. Lamprey LHRH had a preferential LH-releasing activity and a potency 1000 times less than mLHRH. In conclusion. [D-Trp9]GAP1-13 is a selective FSH-releasing peptide of potential clinical value.