Preclinical pharmacological profile of the selective 5-HTIF receptor agonist lasmiditan

Introduction: 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-HTIF receptor agonist. Results: In vitro binding studies show a K-i value of 2.21 nM at the 5-HTIF receptor, compared with K-i values of 1043 nM and 1357 nM at the 5-HTIB and 5-HTID receptors, respectively, a selectivity ratio greater than 470-fold. Lasmiditan showed higher selectivity for the 5-HTIF receptor relative to other 5-HTI receptor subtypes than the first generation 5-HTIF receptor agonist LY334370. Unlike the 5-HTIB/ID receptor agonist sumatriptan, lasmiditan did not contract rabbit saphenous vein rings, a surrogate assay for human coronary artery constriction, at concentrations up to 100 mu M. 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-HTIF receptors in migraine headache therapy.