title: Design, synthesis, and molecular modeling of a novel amide-linked cyclic GnRH analogue cyclo(4-9)[Lys4,D-Trp6,Glu9]GnRH: stimulation of gonadotropin gene expression.
abstract: This report describes the rational design, synthesis, and pharmacological properties of an amide-linked cyclic analogue of gonadotropin-releasing hormone (GnRH) namely Cyclo(4-9)[Lys(4),d-Trp(6),Glu(9)]GnRH. The conformationally restricted analogue is characterized by reduced flexibility of the peptide strand due to the introduction of a beta-turn mimetic through 4,9 residue amide cyclization. The cyclic analogue was found to stimulate gonadotropin gene expression in the goldfish pituitary with similar potency compared to two native forms of GnRH. Simulation studies based on ROE connectivities in linear GnRH and potency of cyclic analogue supports the His(2), Trp(3), Tyr(5) clustering considered important for triggering receptor activation.
authors.affiliation: Department of Chemistry, University of Patras, 26500 Patras, Greece. maria_keram@yahoo.gr
authors.forename: Maria K
authors.initials: MK
authors.lastname: Keramida
authors.forename: Theodore
authors.initials: T
authors.lastname: Tselios
authors.forename: Efthimia
authors.initials: E
authors.lastname: Mantzourani
authors.forename: Kostas
authors.initials: K
authors.lastname: Papazisis
authors.forename: Thomas
authors.initials: T
authors.lastname: Mavromoustakos
authors.forename: Christian
authors.initials: C
authors.lastname: Klaussen
authors.forename: George
authors.initials: G
authors.lastname: Agelis
authors.forename: Spyros
authors.initials: S
authors.lastname: Deraos
authors.forename: Irene
authors.initials: I
authors.lastname: Friligou
authors.forename: Hamid
authors.initials: H
authors.lastname: Habibi
authors.forename: John
authors.initials: J
authors.lastname: Matsoukas
mesh_terms: D000577:Amides / Q000737:chemistry*; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003500:Cyclization; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D005786:Gene Expression Regulation / Q000187:drug effects*; D006054:Goldfish; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006062:Gonadotropins / Q000096:biosynthesis / Q000235:genetics*; D066298:In Vitro Techniques; D008958:Models, Molecular; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D010902:Pituitary Gland / Q000737:chemistry / Q000166:cytology / Q000187:drug effects; D011487:Protein Conformation; D012333:RNA, Messenger / Q000235:genetics
chemical_list: D000577:Amides; D006062:Gonadotropins; D010456:Peptides, Cyclic; D012333:RNA, Messenger; C507813:cyclo(4-9)GnRH, Lys(4)-Trp(6)-Glu(9)-; D007987:Gonadotropin-Releasing Hormone