title: GR138676, a novel peptidic tachykinin antagonist which is potent at NK3 receptors.
abstract: GR138676, a conformationally constrained analogue of neurokinin B, is a novel, potent NK3 receptor antagonist. GR138676 was a competitive antagonist of neurokinin B-dependent arachidonic acid mobilization from prelabelled Chinese hamster ovary cells stably transfected with a human NK3 receptor gene (pKB 8.3) and of contractions induced by senktide in rat portal vein (pKB 8.2). However, GR138676 was also a competitive antagonist of the increase in intracellular calcium evoked by the selective NK1 agonist, GR73632, in the human astrocytoma U373MG cell-line (pKB 8.3). GR138676 had little activity at NK2 receptors, inhibiting binding of the NK2 antagonist radioligand [3H]-GR100679 to Chinese hamster ovary cells transfected with the human ileum NK2 receptor with a pKi of 6.0. In summary, despite its activity at NK1 receptors, GR138676 will be a useful tool for characterizing NK3 receptors as well as defining the physiological and pathophysiological function of this receptor subtype.
authors.affiliation: Department of Pharmacology, Glaxo Research and Development, Ware, Herts, UK.
authors.forename: J M
authors.initials: JM
authors.lastname: Stables
authors.forename: I J
authors.initials: IJ
authors.lastname: Beresford
authors.forename: S
authors.initials: S
authors.lastname: Arkinstall
authors.forename: S J
authors.initials: SJ
authors.lastname: Ireland
authors.forename: D M
authors.initials: DM
authors.lastname: Walsh
authors.forename: P W
authors.initials: PW
authors.lastname: Seale
authors.forename: P
authors.initials: P
authors.lastname: Ward
authors.forename: R M
authors.initials: RM
authors.lastname: Hagan
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001254:Astrocytoma / Q000378:metabolism; D001667:Binding, Competitive; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D006224:Cricetinae; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D015287:Neurokinin B / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D009842:Oligopeptides / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology; D011169:Portal Vein / Q000187:drug effects / Q000502:physiology; D051381:Rats; D018040:Receptors, Neurokinin-1 / Q000819:agonists / Q000502:physiology; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D018042:Receptors, Neurokinin-3 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D013373:Substance P / Q000031:analogs & derivatives / Q000494:pharmacology; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: C092712:GR 138678; D009842:Oligopeptides; D010446:Peptide Fragments; D018040:Receptors, Neurokinin-1; D018041:Receptors, Neurokinin-2; D018042:Receptors, Neurokinin-3; C054724:senktide; C068032:GR 73632; C083380:GR 100679; D016718:Arachidonic Acid; D013373:Substance P; D015287:Neurokinin B; D002118:Calcium