title: A new gonadotropin-releasing hormone (GnRH) superagonist in goldfish: influence of dialkyl-D-homoarginine at position 6 on gonadotropin-II and growth hormone release.
abstract: The two native forms of gonadotropin-releasing hormones (GnRH) present in goldfish, salmon GnRH (sGnRH) and chicken GnRH-II (cGnRH-II), stimulate gonadotropin-II (GTH-II) and growth hormone (GH) release both in vivo and in vitro. In our previous study using perifused goldfish pituitary fragments, many mammalian GnRH antagonists, especially those with D-Arg6, showed weak to strong stimulation of GTH-II and GH release. In the present study, the dose-related stimulation of GTH-II and GH release by [Ac-D(2)-Nal1, 4Cl-D-Phe2, D-Trp3, D-Arg6, Trp7, D-Ala10] mGnRH (analog J) and [Ac-D(2)-Nal1, 4Cl-D-Phe2, D-Trp3, D-hArg(Et2)6, D-Ala10] mGnRH (analog K) was demonstrated; the stimulatory potency of both analogs was significantly lower than that of native sGnRH. In the presence of analogs J and K, cGnRH-II stimulated GTH-II release was significantly suppressed. Further, GTH-II and GH stimulation by 2 microM of analog K was significantly suppressed by a 'true' GnRH antagonist, [Ac-delta 3-Pro1, 4FD-Phe2, D-Trp3,6] mGnRH (analog E). These results indicate that analogs J and K increase GTH-II and GH release in goldfish by acting on GnRH receptors on gonadotrophs and somatotrophs. Since analog K, having [D-hArg(Et2)6], strongly stimulated GTH-II release, the potency of [D-hArg(Et2)6] or [D-hArg(CH2CF3)2(6)] substituted analogs to stimulate GTH-II and GH release from the perifused goldfish pituitary fragments was tested. Among the peptides tested, [D-hArg(Et2)6, Pro9-NHEt] sGnRH had a higher potency in stimulating GTH-II release than any other analog tested in the present or in previous studies. For stimulation of GH release, [D-hArg(Et2)6, Pro9-NHEt] sGnRH and [D-Arg6, Pro9-NHEt] sGnRH were the most potent analogs tested; analogs of mGnRH were less potent than sGnRH, indicating the importance of Trp7, Leu8 residues in the native peptide. These results suggest the importance of [D-Arg6] or alkylated [D-Arg6] in determining the intrinsic activity and potency of GnRH peptides in goldfish.
authors.affiliation: Department of Zoology, University of Alberta, Edmonton, Canada.
authors.forename: C K
authors.initials: CK
authors.lastname: Murthy
authors.forename: R J
authors.initials: RJ
authors.lastname: Turner
authors.forename: J J
authors.initials: JJ
authors.lastname: Nestor
authors.forename: J E
authors.initials: JE
authors.lastname: Rivier
authors.forename: R E
authors.initials: RE
authors.lastname: Peter
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D006054:Goldfish; D007987:Gonadotropin-Releasing Hormone / Q000008:administration & dosage / Q000819:agonists* / Q000031:analogs & derivatives / Q000737:chemistry* / Q000494:pharmacology; D006062:Gonadotropins / Q000378:metabolism*; D013006:Growth Hormone / Q000378:metabolism*; D006709:Homoarginine / Q000737:chemistry*; D008297:Male; D008969:Molecular Sequence Data; D010902:Pituitary Gland / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D006062:Gonadotropins; C091189:LHRH, Ac-2-Nal(1)-4-Cl-Phe(2)-Trp(3)-Arg(Et2)(6)-Ala(10)-; C091188:LHRH, Ac-Nal(1)-4-Cl-Phe(2)-Trp(3)-Arg(6)-Trp(7)-Ala(10)-; D006709:Homoarginine; D007987:Gonadotropin-Releasing Hormone; D013006:Growth Hormone