title: The non-peptide NK-1 receptor antagonist LY303870 inhibits neurogenic dural inflammation in guinea pigs.
abstract: LY303870 is a competitive, high affinity NK-1 receptor antagonist. It was tested in the trigeminal stimulation-induced neurogenic dural inflammation model of migraine. The neurogenic inflammation theory of migraine pain proposes that substance P, acting through NK-1 receptors, causes dural inflammation which enhances migraine pain. LY303870 administration potently inhibited neurogenic dural inflammation as measured by plasma protein extravasation caused by electrical stimulation of the trigeminal ganglion in guinea pigs. It was active in this model when administered via intravenous, oral or inhalation routes. LY306155, the enantiomer of LY303870 with lower affinity for the NK-1 receptor, was much less potent than LY303870 in this model. LY303870, at oral doses of 1, 10 and 100 microg/kg, produced a long, dose-dependent inhibition of dural inflammation, demonstrating a suitable duration of action for a potential use in acute migraine and migraine prophylaxis.
authors.affiliation: The Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, Indiana 46285, USA. lphebus@lilly.com
authors.forename: L A
authors.initials: LA
authors.lastname: Phebus
authors.forename: K W
authors.initials: KW
authors.lastname: Johnson
authors.forename: P W
authors.initials: PW
authors.lastname: Stengel
authors.forename: K L
authors.initials: KL
authors.lastname: Lobb
authors.forename: J A
authors.initials: JA
authors.lastname: Nixon
authors.forename: P A
authors.initials: PA
authors.lastname: Hipskind
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004388:Dura Mater / Q000187:drug effects / Q000378:metabolism; D004558:Electric Stimulation; D006168:Guinea Pigs; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D008881:Migraine Disorders / Q000378:metabolism*; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines / Q000494:pharmacology*; D013237:Stereoisomerism; D018170:Sumatriptan / Q000494:pharmacology
chemical_list: C096759:1-(N-(2-methoxybenzyl)acetylamino)-3-(1H-indol-3-yl)-2-(N-(2-(4-(piperidin-1-yl)piperidin-1-yl)acetyl)amino)propane; D007211:Indoles; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D018170:Sumatriptan