Preclinical pharmacological profile of the selective 5-HT1F receptor agonist lasmiditan.
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.
Nelson
David L
DL
Lilly Research Labs, Eli Lilly & Company, Indianapolis, IN 46285, USA. DLGNelson@lilly.com
Phebus
Lee A
LA
Johnson
Kirk W
KW
Wainscott
David B
DB
Cohen
Marlene L
ML
Calligaro
David O
DO
Xu
Yao-Chang
YC
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
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