To examine the effects of two novel calcitonin gene–related peptide (CGRP) receptor antagonists, ubrogepant and atogepant, on the relaxations induced by α-CGRP in human isolated coronary, cerebral, and middle meningeal arteries. Additionally, the contractile per se responses to atogepant and ubrogepant were compared with the responses to zolmitriptan.

Both ubrogepant and atogepant failed to induced major vasoconstrictor effects at therapeutic concentrations, whereas zolmitriptan elicited concentration-dependent contractions in all vessels. In distal coronary arteries, both gepants antagonized α-CGRP–induced relaxations in a seemingly competitive manner for ubrogepant (pA₂ ubrogepant: 8.82±0.39, R²: 0.87) and non-competitive for atogepant (pK_B atogepant 10 nM: 9.42±0.22; pK_B atogepant 100 nM: 9.11±0.34; pK_B atogepant 1 µM: 8.64±0.21). In cranial (middle meningeal and cerebral) arteries, both gepants antagonized CGRP-induced relaxations more potently than in coronary arteries, with atogepant showing higher potency. The nature of antagonism (competitive or non-competitive) was difficult to establish because both compounds induced potent antagonism.