title: Characterization of LY344864 as a pharmacological tool to study 5-HT1F receptors: binding affinities, brain penetration and activity in the neurogenic dural inflammation model of migraine.
abstract: LY344864 is a selective receptor agonist with an affinity of 6 nM (Ki) at the recently cloned 5-HT1F receptor. It possesses little affinity for the 56 other serotonergic and non-serotonergic neuronal binding sites examined. When examined for its ability to inhibit forskolin-induced cyclic AMP accumulation in cells stably transfected with human 5-HT1F receptors, LY344864 was shown to be a full agonist producing an effect similar in magnitude to serotonin itself. After an intravenous dose of 1 mg/kg, rat plasma LY344864 levels declined with time whereas brain cortex levels remained relatively constant for the first 6 hours after injection. Oral and intravenous LY344864 administration potently inhibited dural protein extravasation caused by electrical stimulation of the trigeminal ganglion in rats. Taken together, these data demonstrate that LY344864 is a selective 5-HT1F receptor agonist that can be used to explore both the in vitro and in vivo functions of this receptor.
authors.affiliation: Eli Lilly and Co., Lilly Corporate Center, 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: J M
authors.initials: JM
authors.lastname: Zgombick
authors.forename: P J
authors.initials: PJ
authors.lastname: Gilbert
authors.forename: K
authors.initials: K
authors.lastname: Van Belle
authors.forename: V
authors.initials: V
authors.lastname: Mancuso
authors.forename: D L
authors.initials: DL
authors.lastname: Nelson
authors.forename: D O
authors.initials: DO
authors.lastname: Calligaro
authors.forename: A D
authors.initials: AD
authors.lastname: Kiefer
authors.forename: T A
authors.initials: TA
authors.lastname: Branchek
authors.forename: M E
authors.initials: ME
authors.lastname: Flaugh
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D002227:Carbazoles / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D004195:Disease Models, Animal; D004388:Dura Mater / Q000378:metabolism / Q000473:pathology*; D005464:Fluorobenzenes / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation; D008297:Male; D008881:Migraine Disorders / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D051381:Rats; D011916:Rats, Inbred F344; D011985:Receptors, Serotonin / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D000096642:Receptor, Serotonin, 5-HT1F
chemical_list: D002227:Carbazoles; D005464:Fluorobenzenes; D011985:Receptors, Serotonin; D011994:Recombinant Proteins; D017366:Serotonin Receptor Agonists; D000096642:Receptor, Serotonin, 5-HT1F; C109453:LY 344864