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Abstract Details

Characterization of the Effects of the Calcitonin Gene–Related Peptide (CGRP) Receptor Antagonists, Atogepant and Ubrogepant, on Isolated Human Coronary, Cerebral, and Middle Meningeal Arteries
Headache
S20 - Headache Imaging and Physiology and Episodic Syndromes Associated with Migraine (3:52 PM-4:03 PM)
003
CGRP, a neuropeptide released from the trigeminal fibers, plays an important role in migraine pathophysiology. 

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.

Human coronary arteries were obtained from 8 donor hearts. Human cerebral (cortex) arteries and middle meningeal arteries were removed peri-operatively from patients undergoing neurosurgery (7 and 5 subjects, respectively). All requisite ethics-related approvals were obtained. The relaxant effect of human α-CGRP was examined by cumulative application of increasing concentrations (1 pM–100 nM) of the peptide in the absence or presence of ubrogepant or atogepant. Vessels were precontracted with KCl (30 mM) before α-CGRP was added. For each segment, the maximum vasodilator effect (Emax) was calculated. Per se contractile responses to atogepant, ubrogepant, and vehicle (dimethyl sulfoxide) were compared with contractile responses elicited by 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 (pKB atogepant 10 nM: 9.42±0.22; pKB atogepant 100 nM: 9.11±0.34; pKB 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.

Ubrogepant and atogepant were devoid of vasoconstrictive properties at therapeutic concentrations and the blockade of the CGRP receptor was more potent in cranial than in coronary arteries. 
Authors/Disclosures

PRESENTER
No disclosure on file
No disclosure on file
No disclosure on file
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Lars Edvinsson No disclosure on file