Preclinical pharmacological profile of the selective 5-HT1F receptor agonist lasmiditan
- 15 June 2010
- journal article
- Published by SAGE Publications in Cephalalgia
- Vol. 30 (10), 1159-1169
- https://doi.org/10.1177/0333102410370873
Abstract
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.Keywords
This publication has 29 references indexed in Scilit:
- Advances in the basic and clinical science of migraineAnnals of Neurology, 2009
- Migraine — Current Understanding and TreatmentNew England Journal of Medicine, 2002
- Contractile 5‐HT1B receptors in human cerebral arteries: pharmacological characterization and localization with immunocytochemistryBritish Journal of Pharmacology, 1999
- Regulation of Calcitonin Gene-Related Peptide Secretion by a Serotonergic Antimigraine DrugJournal of Neuroscience, 1999
- 5-HT1F receptor agonists inhibit neurogenic dural inflammation in guinea pigsNeuroReport, 1997
- Cloning and Characterization of The Guinea Pig 5-HT 1F Receptor Subtype: a Comparison of the Pharmacological Profile to the Human Species HomologNeuropharmacology, 1997
- Serotonin and MigraineAnnals of the New York Academy of Sciences, 1990
- Sumatriptan (GR 43175) interacts selectively with 5-HT1B and 5-HT1D binding sitesEuropean Journal of Pharmacology, 1989
- GR43175, a selective agonist for the 5‐HT1‐like receptor in dog isolated saphenous veinBritish Journal of Pharmacology, 1988
- Serotonin and the Vascular SystemDrugs, 1986