Ubrogepant and Atogepant Inhibit Vasodilation in Cerebral Arteries

Although they have not demonstrated vasoconstrictive properties in human coronary arteries, both ubrogepant and atogepant have inhibitive effects on calcitonin gene-related peptide (CGRP)-mediated vasodilatory responses in intracranial vs distal human coronary arteries, according to a study recently published in Cephalalgia.

This study included middle meningeal arteries from 1 man and 5 women (mean age 45±3 years), as well as cerebral arteries from 3 men and 4 women (mean age 60±4 years). These neurosurgical procedures were completed in a single center in Sweden. In addition, coronary arteries were collected from 4 men and 4 women (age 41±3 years). The effects of ubrogepant and atogepant on CGRP-induced relaxations were investigated. These drugs were also compared with zolmitriptan in terms of contractile responses in distal and proximal coronary arteries. The maximum vasodilator effect (defined as the observed response at maximum applied CGRP) was calculated for each segment, with concentration response curves plotted using nonlinear regression. 

Both ubrogepant and atogepant inhibited CGRP-mediated relaxations more in intracranial arteries than in distal coronary arteries, though a higher potency was observed with atogepant. A significant rightward shift on concentration response curves was observed with both ubrogepant (10 nM, P =.01; 100 nM, P  =.002; 1 µM, P =.003) and atogepant (10 nM, P =.003; 100 nM, P =.001; 1 µM, P <.001) in distal coronary arteries. Coronary artery Schild plots showed a competitive antagonism with ubrogepant (slope was similar to unity, 0.87±0.17) and a noncompetitive antagonism with atogepant (slope was significantly less than unity, 0.55±0.01). Concentration-dependent contractions were observed with zolmitriptan in distal (potency of agonist 7.10±0.13; maximum vasodilator effect 72±33%; n=6) and proximal (potency of agonist 5.53±0.32; maximum vasodilator effect 38±12%; n=6), while neither ubrogepant or atogepant were associated with a vasoconstrictor effect in coronary arteries.

This study was limited by the inability to draw firm conclusions from Schild plot observations.

The study researchers concluded that “both atogepant and ubrogepant effectively inhibit the CGRP-vasodilatory responses in human meningeal, cerebral, and coronary arteries.” Furthermore, they indicated that both drugs are “devoid of vasoconstrictive properties in [human coronary arteries].”

Disclosure: This clinical trial was supported by Allergran. Please see the original reference for a full list of authors’ disclosures.

Reference
Rubio-Beltran E, Chan KY, Danser AJ, Maassen Van Den Brink A, Edvinsson L. Characterisation of the calcitonin gene-related peptide receptor antagonists ubrogepant and atogepant in human isolated coronary, cerebral and middle meningeal arteries [published online November 1, 2019]. Cephalalgia. doi: 10.1177/0333102419884943