title: Identification of new gonadotrophin-releasing hormone partial agonists.
abstract: GnRH agonists or antagonists are currently utilized as therapeutic agents in a number of diseases. A side-effect of prolonged treatment with GnRH analogues is hypoestrogenism. In this study, we tested the in vitro potency of different GnRH analogues originally found to be partial agonists (i.e. analogues with decreased efficacy for activating or stimulating their cognate receptor) as well as novel analogues, to identify compounds that might potentially be useful for partial blockade of gonadotrophin release. Cultured COS-7 cells transiently expressing the rat or human GnRH receptor (GnRHR) were exposed to increasing concentrations (10(-8) to 10(-5) M) of GnRH analogues (c(4-10)[Asp4,DNal6,Dpr10]-GnRH; c(4-10) [Dpr4,DNal6,Asp10]-GnRH; c(4-10)[Cys(4,10),DNal6]-GnRH; c[Eaca1,DNal6]-GnRH; c[Gly1,DNal6]-GnRH; c[betaAla1,DTrp6]-GnRH; c[Dava1,DNal6]-GnRH; c[Gaba1, DNal6]-GnRH), and the ability of these analogues to provoke or antagonize GnRH-stimulated inositol phosphate production was assessed. With both human and rat GnRHRs, c[Eaca1,DNal6]-GnRH, c[Gly1,DNal6]-GnRH, c[betaAla1,DTrp6]-GnRH and c[Dava1,DNal6]-GnRH exhibited partial agonist activity (35-87% of the maximal efficacy shown by 10(-6) M GnRH), whereas c[Gaba1,DNal6]-GnRH behaved as a partial agonist with the human GnRHR and as full agonist with the rat GnRHR. c(4-10)[Asp4, DNal6,Dpr10]-GnRH and c(4-10)[Dpr4,DNal6,Asp10]-GnRH exhibited full antagonist activity with both GnRHRs, and c(4-10) [Cys(4,10),DNal6]-GnRH was a weak, partial agonist with the human GnRHR and a full antagonist with the rat GnRHR. With the exception of c[Gaba1,DNal6]-GnRH stimulation of the human GnRHR, and c[Dava1,DNal6]-GnRH and c[Gaba1, DNal6]-GnRH stimulation of the rat GnRHR, all partial agonists also exhibited antagonist activity in the presence of the exogenous full agonist. The results demonstrate that structurally similar analogues display variable potencies and efficacies in vitro for a specific GnRHR as well as for the human versus the rat GnRHR. Their ultimate in vivo usefulness to treat clinical conditions in which complete suppression of gonadotroph activity is not required remains to be investigated.
authors.affiliation: Oregon National Primate Research Center, Oregon Health and Science University, 505 NW 185th Avenue, Beaverton, Oregon 97006, USA.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Leaños-Miranda
authors.forename: Alfredo
authors.initials: A
authors.lastname: Ulloa-Aguirre
authors.forename: Laura A
authors.initials: LA
authors.lastname: Cervini
authors.forename: Jo Ann
authors.initials: JA
authors.lastname: Janovick
authors.forename: Jean
authors.initials: J
authors.lastname: Rivier
authors.forename: P Michael
authors.initials: PM
authors.lastname: Conn
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D002064:Buserelin / Q000378:metabolism; D019556:COS Cells; D002522:Chlorocebus aethiops; D004305:Dose-Response Relationship, Drug; D007987:Gonadotropin-Releasing Hormone / Q000819:agonists* / Q000032:analysis* / Q000378:metabolism; D006727:Hormone Antagonists / Q000032:analysis; D006801:Humans; D007295:Inositol Phosphates / Q000096:biosynthesis; D011485:Protein Binding; D051381:Rats; D011966:Receptors, LHRH / Q000378:metabolism; D014162:Transfection
chemical_list: D006727:Hormone Antagonists; D007295:Inositol Phosphates; D011966:Receptors, LHRH; D007987:Gonadotropin-Releasing Hormone; D002064:Buserelin