title: Preclinical pharmacological profile of the selective 5-HT1F receptor agonist lasmiditan.
abstract: BACKGROUND
  Lasmiditan (also known as COL-144 and LY573144; 2,4,6-trifluoro-N-[6-[(1-methylpiperidin-4-yl)carbonyl]pyridin-2yl]benzamide) is a high-affinity, highly selective serotonin (5-HT) 5-HT(1F) receptor agonist.
  
  
  RESULTS
  In vitro binding studies show a K(i) value of 2.21 nM at the 5-HT(1F) receptor, compared with K(i) values of 1043 nM and 1357 nM at the 5-HT(1B) and 5-HT(1D) receptors, respectively, a selectivity ratio greater than 470-fold. Lasmiditan showed higher selectivity for the 5-HT(1F) receptor relative to other 5-HT(1) receptor subtypes than the first generation 5-HT(1F) receptor agonist LY334370. Unlike the 5-HT(1B/1D) receptor agonist sumatriptan, lasmiditan did not contract rabbit saphenous vein rings, a surrogate assay for human coronary artery constriction, at concentrations up to 100 µM. In two rodent models of migraine, oral administration of lasmiditan potently inhibited markers associated with electrical stimulation of the trigeminal ganglion (dural plasma protein extravasation, and induction of the immediate early gene c-Fos in the trigeminal nucleus caudalis).
  
  
  CONCLUSIONS
  Lasmiditan presents a unique pyridinoyl-piperidine scaffold not found in any other antimigraine class. Its chemical structure and pharmacological profile clearly distinguish it from the triptans. The potency and selectivity of lasmiditan make it ideally suited to definitively test the involvement of 5-HT(1F) receptors in migraine headache therapy.
authors.affiliation: Lilly Research Labs, Eli Lilly & Company, Indianapolis, IN 46285, USA. DLGNelson@lilly.com
authors.forename: David L
authors.initials: DL
authors.lastname: Nelson
authors.forename: Lee A
authors.initials: LA
authors.lastname: Phebus
authors.forename: Kirk W
authors.initials: KW
authors.lastname: Johnson
authors.forename: David B
authors.initials: DB
authors.lastname: Wainscott
authors.forename: Marlene L
authors.initials: ML
authors.lastname: Cohen
authors.forename: David O
authors.initials: DO
authors.lastname: Calligaro
authors.forename: Yao-Chang
authors.initials: YC
authors.lastname: Xu
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D012668:Trigeminal Ganglion / Q000187:drug effects; D000096642:Receptor, Serotonin, 5-HT1F
chemical_list: D001549:Benzamides; D007211:Indoles; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D000096642:Receptor, Serotonin, 5-HT1F; C108218:4-fluoro-N-(3-(1-methyl-4-piperidinyl)-1H-indol-5-yl)benzamide