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.2019 Dec;176(24):4681-4695.
doi: 10.1111/bph.14832. Epub 2019 Nov 7.

Characterization of binding, functional activity, and contractile responses of the selective 5-HT1F receptor agonist lasmiditan

Affiliations

Characterization of binding, functional activity, and contractile responses of the selective 5-HT1F receptor agonist lasmiditan

Eloísa Rubio-Beltrán et al. Br J Pharmacol.2019 Dec.

Abstract

Background and purpose: Triptans 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 approach: Binding 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 results: Lasmiditan 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 implications: Lasmiditan is a selective 5-HT1F receptor agonist devoid of vasoconstrictor activity. This may represent a cardiovascular safety advantage when compared to the triptans.

© 2019 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

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Conflict of interest statement

E.R.B. and A.L.R. received travel support from Eli Lilly/CoLucid. E.Z. and C.M.V. received consultation fees from Eli Lilly/CoLucid. L.M., M.R.G. and P.B.S. performed experiments under a research contract with Eli Lilly/CoLucid. J.K. is former employee of Eli Lilly/CoLucid. K.W.J. is employee of Eli Lilly. A.M.v.d.B. received research grants and/or consultation fees from Amgen/Novartis, Eli Lilly/CoLucid, Teva, and ATI. All other authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Summary of the agonist profiles (pEC50 > 7) of the antimigraine drugs tested on the 5‐HT1B, 5‐HT1D, and 5‐HT1F receptors. Redrawn from Rubio‐Beltran, Labastida‐Ramirez, Villalon, and MaassenVanDenBrink (2018)
Figure 2
Figure 2
Contractile responses to lasmiditan and sumatriptan (1 nM–100 μM) in the isolated human proximal (left) and distal (right) coronary arteries; *P < .05, significantly different as indicated;n = 6 each
Figure 3
Figure 3
Contractile responses to sumatriptan and lasmiditan (1 nM–100 μM) in the absence (left) and presence (right) of a threshold precontraction with U46619 (1–10 nM) in the isolated human internal mammary arteries with (upper panel,n = 5) and without (lower panel,n = 7) functional endothelium; *P < .05, significantly different as indicated
Figure 4
Figure 4
Contractile responses to sumatriptan and lasmiditan (1 nM–100 μM) in the isolated human middle meningeal arteries; *P < .05, significantly different as indicated;n = 6 each
Figure 5
Figure 5
Contractile responses to sumatriptan and lasmiditan (1 nM–100 μM) in the internal mammary artery, after preincubation with the clinically relevant concentration of sumatriptan (0.3 μM) or lasmiditan (1 μM), and followed by a concentration–response curve to lasmiditan or sumatriptan, respectively (n = 6 each)
Figure 6
Figure 6
Correlation between the pKi values obtained in our study and the contractile potency of lasmiditan, triptans (sumatriptan, zolmitriptan, naratriptan, rizatriptan, eletriptan, frovatriptan, donitriptan, and avitriptan), and other 5‐HT receptors ligands (ergotamine, alniditan, 5­HT, and 5‐carboxamidotryptamine) in human isolated coronary arteries; N.S., non‐significant;*P < .05, significant correlation
Figure 7
Figure 7
Changes in the left circumflex (LCX) coronary artery diameter (a), carotid artery diameter (b), and mean arterial blood pressure (c) after the continuous infusion of lasmiditan and sumatriptan (0.03–11.13 mg·kg−1 each) or the corresponding infusion volumes of vehicle in female beagle dogs (n = 6 each). *P < .05, significantly different from vehicle; post hoc analysis (see methods)
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