Abstract
Background and PurposeTriptans are 5‐HT1B/1D receptor agonists (that also display 5‐HT1F receptor affinity) with antimigraine action, contraindicated in patients with coronary artery disease due to their vasoconstrictor properties. Conversely, lasmiditan was developed as an antimigraine 5‐HT1F receptor agonist. To assess the selectivity and cardiovascular effects of lasmiditan, we investigated the binding, functional activity, and in vitro/in vivo vascular effects of lasmiditan and compared it to sumatriptan.Experimental ApproachBinding and second messenger activity assays of lasmiditan and other serotoninergic agonists were performed for human 5‐HT1A, 5‐HT1B, 5‐HT1D, 5‐ht1E, 5‐HT1F, 5‐HT2A, 5‐HT2B, and 5‐HT7 receptors, and the results were correlated with their potency to constrict isolated human coronary arteries (HCAs). Furthermore, concentration–response curves to lasmiditan and sumatriptan were performed in proximal and distal HCA, internal mammary, and middle meningeal arteries. Finally, anaesthetized female beagle dogs received i.v. infusions of lasmiditan or sumatriptan in escalating cumulative doses, and carotid and coronary artery diameters were measured.Key ResultsLasmiditan showed high selectivity for 5‐HT1F receptors. Moreover, the functional potency of the analysed compounds to inhibit cAMP increase through 5‐HT1B receptor activation positively correlated with their potency to contract HCA. In isolated human arteries, sumatriptan, but not lasmiditan, induced contractions. Likewise, in vivo, sumatriptan decreased coronary and carotid artery diameters at clinically relevant doses, while lasmiditan was devoid of vasoconstrictor activity at all doses tested.Conclusions and ImplicationsLasmiditan is a selective 5‐HT1F receptor agonist devoid of vasoconstrictor activity. This may represent a cardiovascular safety advantage when compared to the triptans.
Highlights
Migraine is a neurological disease characterized by throbbing unilateral headaches of moderate to severe intensity, accompanied by nausea, vomiting, photophobia, and/or phonophobia (Headache Classification Committee of the International Headache Society, 2018)
Considering the increased cardiovascular risk of migraine patients (Buse, Reed, Fanning, Kurth, & Lipton, 2017; Kurth et al, 2016; Sacco & Kurth, 2014; Schurks et al, 2009), and the presence of 5‐HT1F receptors in the vasculature (Bouchelet, Case, Olivier, & Hamel, 2000; Bouchelet, Cohen, Case, Séguéla, & Hamel, 1996; Nilsson et al, 1999), it is important to determine whether lasmiditan lacks affinity for human 5‐HT1B receptors and whether activation of 5‐HT1F receptors will result in vasoconstrictive responses
The aim of this study was to investigate the pharmacological properties of lasmiditan and in particular (a) to assess the selectivity and functional activity of lasmiditan, triptans, and other 5‐HT receptor ligands on various human 5‐HT receptors; (b) to analyse its potential to induce vasoconstriction in in vitro and in vivo preclinical models; and (c) to compare our findings with lasmiditan to those obtained with sumatriptan, one of the most prescribed triptans to acutely treat migraine
Summary
Migraine is a neurological disease characterized by throbbing unilateral headaches of moderate to severe intensity, accompanied by nausea, vomiting, photophobia, and/or phonophobia (Headache Classification Committee of the International Headache Society, 2018). Considering the increased cardiovascular risk of migraine patients (Buse, Reed, Fanning, Kurth, & Lipton, 2017; Kurth et al, 2016; Sacco & Kurth, 2014; Schurks et al, 2009), and the presence of 5‐HT1F receptors in the vasculature (Bouchelet, Case, Olivier, & Hamel, 2000; Bouchelet, Cohen, Case, Séguéla, & Hamel, 1996; Nilsson et al, 1999), it is important to determine whether lasmiditan lacks affinity for human 5‐HT1B receptors and whether activation of 5‐HT1F receptors will result in vasoconstrictive responses On this basis, the aim of this study was to investigate the pharmacological properties of lasmiditan and in particular (a) to assess the selectivity and functional activity of lasmiditan, triptans, and other 5‐HT receptor ligands on various human 5‐HT receptors; (b) to analyse its potential to induce vasoconstriction in in vitro (isolated human proximal and distal coronary, internal mammary, and middle meningeal arteries) and in vivo (carotid and coronary artery diameters in anesthetized dogs) preclinical models; and (c) to compare our findings with lasmiditan to those obtained with sumatriptan, one of the most prescribed triptans to acutely treat migraine. In vivo, sumatriptan decreased coronary and carotid artery diameters at clinically relevant doses, while lasmiditan was devoid of vasoconstrictor activity at all doses tested
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