title: Characterization of 12 GnRH peptide agonists - a kinetic perspective.
abstract: OBJECTIVE
  Drug-target residence time is an important, yet often overlooked, parameter in drug discovery. Multiple studies have proposed an increased residence time to be beneficial for improved drug efficacy and/or longer duration of action. Currently, there are many drugs on the market targeting the gonadotropin-releasing hormone (GnRH) receptor for the treatment of hormone-dependent diseases. Surprisingly, the kinetic receptor-binding parameters of these analogues have not yet been reported. Therefore, this project focused on determining the receptor-binding kinetics of 12 GnRH peptide agonists, including many marketed drugs.
  
  
  METHODS
  A novel radioligand-binding competition association assay was developed and optimized for the human GnRH receptor with the use of a radiolabelled peptide agonist, [(125) I]-triptorelin. In addition to radioligand-binding studies, a homogeneous time-resolved FRET Tag-lite™ method was developed as an alternative assay for the same purpose.
  
  
  RESULTS
  Two novel competition association assays were successfully developed and applied to determine the kinetic receptor-binding characteristics of 12 high-affinity GnRH peptide agonists. Results obtained from both methods were highly correlated. Interestingly, the binding kinetics of the peptide agonists were more divergent than their affinities with residence times ranging from 5.6 min (goserelin) to 125 min (deslorelin).
  
  
  CONCLUSIONS
  Our research provides new insights by incorporating kinetic, next to equilibrium, binding parameters in current research and development that can potentially improve future drug discovery targeting the GnRH receptor.
authors.affiliation: Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, The Netherlands.
authors.forename: Indira
authors.initials: I
authors.lastname: Nederpelt
authors.affiliation: Global Drug Discovery, Lead Discovery Berlin, Bayer Healthcare Pharmaceuticals, Berlin, Germany.
authors.forename: Victoria
authors.initials: V
authors.lastname: Georgi
authors.affiliation: Global Drug Discovery, Lead Discovery Berlin, Bayer Healthcare Pharmaceuticals, Berlin, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Schiele
authors.affiliation: Global Drug Discovery, Lead Discovery Berlin, Bayer Healthcare Pharmaceuticals, Berlin, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Nowak-Reppel
authors.affiliation: Global Drug Discovery, Lead Discovery Berlin, Bayer Healthcare Pharmaceuticals, Berlin, Germany.
authors.forename: Amaury E
authors.initials: AE
authors.lastname: Fernández-Montalván
authors.affiliation: Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, The Netherlands.
authors.forename: Adriaan P
authors.initials: AP
authors.lastname: IJzerman
authors.affiliation: Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, The Netherlands.
authors.forename: Laura H
authors.initials: LH
authors.lastname: Heitman
mesh_terms: D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D016466:CHO Cells; D003412:Cricetulus; D005456:Fluorescent Dyes / Q000494:pharmacology; D007987:Gonadotropin-Releasing Hormone / Q000819:agonists* / Q000031:analogs & derivatives*; D006801:Humans; D007457:Iodine Radioisotopes; D007700:Kinetics; D011869:Radioligand Assay / Q000379:methods*; D011966:Receptors, LHRH / Q000819:agonists*; D017329:Triptorelin Pamoate / Q000494:pharmacology*
chemical_list: D005456:Fluorescent Dyes; C484844:GNRHR protein, human; D007457:Iodine Radioisotopes; D011966:Receptors, LHRH; D017329:Triptorelin Pamoate; D007987:Gonadotropin-Releasing Hormone