title: L-733,060, a novel tachykinin NK1 receptor antagonist; effects in [Ca2+]i mobilisation, cardiovascular and dural extravasation assays.
abstract: This study investigated the properties of a novel piperidine ether-based tachykinin NK1 receptor antagonist L-733,060, ((2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-phenyl piperidine and its 2R,3R-enantiomer L-733,061 on [Ca2+]i mobilisation in Chinese hamster ovary cells transfected with human tachykinin NK1 receptors, compared to their effects in rodent cardiovascular and neurogenic plasma extravasation assays. Using FURA-2-imaging techniques, L-733,060 inhibited substance P-induced [Ca2+]i mobilisation with an estimated affinity of 0.8 nM whereas L-733,061 (30-300 nM) did not. No significant effects of L-733,060 were observed on mean arterial blood pressure or heart rate in conscious or anaesthetised rats at doses of < 3000 micrograms kg-1 i.v. L-733,060 also stereoselectively inhibited neurogenic plasma extravasation in rat dura produced by electrical stimulation of trigeminal nerves with an ID50 of 212 +/- 19 micrograms kg-1 i.v. Thus, L-733,060 is a novel antagonist of human tachykinin NK1 receptors which stereoselectively inhibits neurogenic plasma extravasation at doses that do not cause adverse cardiovascular effects.
authors.affiliation: Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, UK.
authors.forename: G R
authors.initials: GR
authors.lastname: Seabrook
authors.forename: S L
authors.initials: SL
authors.lastname: Shepheard
authors.forename: D J
authors.initials: DJ
authors.lastname: Williamson
authors.forename: P
authors.initials: P
authors.lastname: Tyrer
authors.forename: M
authors.initials: M
authors.lastname: Rigby
authors.forename: M A
authors.initials: MA
authors.lastname: Cascieri
authors.forename: T
authors.initials: T
authors.lastname: Harrison
authors.forename: R J
authors.initials: RJ
authors.lastname: Hargreaves
authors.forename: R G
authors.initials: RG
authors.lastname: Hill
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism*; D002199:Capillary Permeability / Q000187:drug effects*; D006224:Cricetinae; D005849:Gerbillinae; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D008297:Male; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018040:Receptors, Neurokinin-1 / Q000096:biosynthesis; D013237:Stereoisomerism; D014162:Transfection
chemical_list: D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D018040:Receptors, Neurokinin-1; C103788:3-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidine; D002118:Calcium