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, GAP 1−13 had a preferential FSH-releasing activity. To decrease enzymatic degradation, analogs of GAP 1–13 with D-amino acid substitutions were synthesized. The activities were tested in ovariectomized, estrogen-progesterone primed (OEP) rats and compared with those of GAP 1−13 , mammalian (m), chicken II (eII), and lamprey (1) LHRH. The peptides were injected (IV) into conscious, OEP rats and blood samples were obtained via the jugular catheter. [D-Trp 9 ]GAP 1–13 selectively stimulated FSH release at a dose of 1 μg. Multiple injections of this analog (10 μg every 30 min for 5 injections) induced a marked elevation of plasma FSH values which peaked ( p 9 ]GAP 1–13 had no effect on LH and prolactin (PRL) release after either single or multiple injections. These doses of [DAla 4 ] GAP 1–13 had no effect on the release of FSH, LH or PRL. Both human GAP 1–13 and its [D-Trp 9 ] analog exerted a selective FSH-releasing effect at a dose of 10 μg, however, the [D-Trp 9 ] analog was more potent than GAP 1–13 on FSH release. The potency of [D-Trp 9 ]GAP 1–13 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-Trp 9 ]GAP 1–13 is a selective FSH-releasing peptide of potential clinical value.