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Preclinical pharmacological profile of the selective 5-HT1F 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-HT1F receptor agonist. Results: In vitro binding studies show a Ki value of 2.21 nM at the 5-HT1F receptor, compared with Ki values of 1043 nM and 1357 nM at the 5-HT1B and 5-HT1D receptors, respectively, a selectivity ratio greater than 470-fold. Lasmiditan showed higher selectivity for the 5-HT1F receptor relative to other 5-HT1 receptor subtypes than the first generation 5-HT1F receptor agonist LY334370. Unlike the 5-HT1B/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-HT1F receptors in migraine headache therapy.