Background and Purpose:Triptans are 5-HT 1B/1D receptor agonists (that also display 5-HT 1F 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-HT 1F 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-HT 1A , 5-HT 1B , 5-HT 1D , 5-ht 1E , 5-HT 1F , 5-HT 2A , 5-HT 2B , and 5-HT 7 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-HT 1F receptors. Moreover, the functional potency of the analysed compounds to inhibit cAMP increase through 5-HT 1B 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. ---This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. Conclusions and Implications:Lasmiditan is a selective 5-HT 1F receptor agonist devoid of vasoconstrictor activity. This may represent a cardiovascular safety advantage when compared to the triptans. SUPPORTING INFORMATIONAdditional supporting information may be found online in the Supporting Information section at the end of the article. How to cite this article: Rubio-Beltrán E, Labastida-Ramírez A, Haanes KA, et al. Characterization of binding, functional activity, and contractile responses of the selective 5-HT 1F receptor agonist lasmiditan. Br J Pharmacol. 2019; https://doi.

In contrast to cyclooxygenase-1 (COX-1), the basal expression of renal cyclooxygenase-2 (COX-2) varies among species. High basal levels of COX-2 in the renal cortex and papilla in dogs compared with monkeys suggest that COX-2 inhibition may lead to distinct nephrotoxic responses. In this study, we compared the renal effects of COX inhibition between dogs and cynomolgus monkeys (n = 6/group) following the administration of naproxen sodium, a non-selective COX-1/COX-2 inhibitor. Dogs and monkeys were treated with 50 or 150 mg/kg/day naproxen sodium, respectively, for 2 to 6 weeks. Naproxen doses used in this study resulted in equivalent inhibition of COX activity in both species as measured by reductions in urinary prostaglandin E2 (PGE2) and 6-keto-PGF1-alpha levels. There was prominent reduction in renal blood flow (43%) and urinary sodium excretion (62%) in dogs but no alterations in renal blood flow and only minimal change (19%) in urinary sodium excretion in monkeys. The canine but not monkey kidney showed prominent COX-2 expression in the macula densa, thick ascending limb of Henle and papillary interstitial cells by immunohistochemistry. After treatment, the canine but not monkey kidneys had mild to moderate renal tubular atrophy and interstitial fibrosis and renal papillary necrosis. Obstructive nephropathy secondary to intra-tubular drug accumulation was seen in monkeys but not in dogs. Collectively, these data demonstrate species differences in the renal response to COX inhibition. The nature of functional and morphologic changes suggests a more prominent role of COX-2 in renal hemodynamics and natriuresis in dogs than in monkeys.

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Rats develop translatable pulmonary arterial hypertension (PAH) after exposure to the VEGF antagonist semaxanib (SU5416) concurrent with hypoxia. Sildenafil is used clinically for PAH and as a positive control in this preclinical model. A longitudinal analysis was constructed by pooling data from discrete rat PAH studies conducted over an 8-year period to evaluate the stability and reproducibility of the SU5416/Hypoxia rodent model as well as the response to sildenafil. Sprague-Dawley rats were administered SU5416 on Day 1 and subsequently maintained in a low oxygen environment for 28 days. Sildenafil was given as a positive control in either prevention or treatment mode. Pulmonary hemodynamics were obtained on the final day as appropriate by design; hearts were also assessed for right ventricular hypertrophy. Prevention studies (≥17) were terminated following 28 days of hypoxia while most treatment studies (≥17) had a protocol-defined period of normoxia following hypoxia. In prevention studies, the mean of both systolic pulmonary arterial pressure (sPAP) and the right ventricular hypertrophy Fulton’s Index (FI) remained consistent across studies over the 7-year period: sPAP: PAH vehicle control (PAH-VC) 70 ± 19 mmHg (n = 190), sildenafil 51 ± 15 mmHg (n = 165), p<.05; FI: PAH-VC 0.5573 ± 0.1048 (n = 210), sildenafil 0.4984 ± 0.1007 (n = 172), p<.05. Sildenafil elicited mean reductions in sPAP of 28% and FI of 11% over the 7-year period. Mean survival rate was comparable for PAH-VC (96%) and sildenafil groups (99%).In treatment studies, the mean of both sPAP and FI remained consistent across studies over the 8-year period: sPAP: PAH-VC 89 ± 24 mmHg (n = 148) vs. sildenafil 67 ± 22 mmHg (n = 168), p<.05 vs PAH-VC; FI: PAH-VC 0.5938 ± 0.0944 (n = 168) vs. sildenafil 0.5336 ± 0.1077 (n = 173), p<.05 vs PAH-VC. Sildenafil elicited mean reductions in sPAP of 25% and FI of 10% over the 8-year period. Mean survival rate was comparable for PAH-VC (91%) and sildenafil groups (95%).The effects of sildenafil on reduction of PAH were stable and of similar magnitude in both prevention and treatment studies over an 8-year period. Thus, this longitudinal analysis indicates a reproducible and consistent effect of both the SU5416/Hypoxia PAH model and the use of sildenafil as a positive control.

Previous work has demonstrated the development of increased pulmonary artery pressures, hypertrophy of the pulmonary arterial vascular smooth muscle, and proliferation of the endothelial vascular lumen in rats following extended exposure to hypoxia and VEGF‐receptor antagonists. We validated this model of pulmonary arterial hypertension (PAH) by evaluating its utility as a clinically relevant paradigm to determine the efficacy of test articles against PAH. Male SD rats (240–370 g) were kept inside a hypoxic tent. Atmospheric oxygen was reduced to 13.5% using an oxygen scrubber. Rats received a single dose of semaxanib (200 mg/kg, s.c.) and were maintained inside the tent for 3 weeks. Rats received oral doses of vehicle (20% cyclodextrin, 10mL/kg once daily), bosentan (BS‐ 300mg/kg once daily) or sildenafil (SL‐ 30mg/kg twice daily). At day 21, pulmonary and systemic arterial pressures and thoracic organ weights were measured. BS and SL‐treated rats exhibited systolic, diastolic and mean pulmonary arterial pressures (21 and 19; 16 and 15; 18 and 17 mmHg, respectively) that were significantly lower compared to the vehicle (30, 22 and 26 mmHg, respectively). There was a trend toward decreased right ventricle to left ventricle weight ratio when comparing BS and SL with the vehicle. There were no significant differences in mean arterial pressure among rats treated with BS and SL as compared to vehicle. In summary, oral administration of BS and SL reduces PAH induced semaxanib and a low oxygen environment in a clinically relevant model.