Blocking the CGRP Receptor: Differences across Human Vascular Beds

Abstract

Multiple drugs targeting the calcitonin gene-related peptide (CGRP) receptor have been developed for the treatment of migraine. Here, the effect of the small-molecule CGRP receptor antagonist zavegepant (0.1 nM–1 µM) on CGRP-induced relaxation in isolated human coronary arteries (HCAs) was investigated. A Schild plot was constructed and a pA2 value was calculated to determine the potency of zavegepant. The potency and Schild plot slopes of atogepant, olcegepant, rimegepant, telcagepant, ubrogepant and zavegepant in HCAs and human middle meningeal arteries (HMMAs), obtained from our earlier studies, were compared. Zavegepant shifted the concentration–response curve to CGRP in HCAs. The corresponding Schild plot slope was not different from unity, resulting in a pA2 value of 9.92 ± 0.24. No potency difference between HCAs and HMMAs was observed. Interestingly, olcegepant, atogepant and rimegepant, with a Schild plot slope < 1 in HCAs, were all >1 log unit more potent in HMMAs than in HCAs, while telcagepant, ubrogepant and zavegepant, with a Schild plot slope not different from unity, showed similar (<1 log difference) potency across both tissues. As a Schild plot slope < 1 may point to the involvement of multiple receptors, it is important to further identify the receptors involved in the relaxation to CGRP in HCAs, which may be used to improve the cardiovascular safety of future antimigraine drugs.

A Comprehensive Review of the Mechanism, Efficacy, Safety, and Tolerability of Ubrogepant in the Treatment of Migraine

“…As a CGRP receptor antagonist, ubrogepant blocks this receptor, preventing CGRP from binding and exerting its effects. Consequently, there is a reduction in blood vessel dilation, nerve fiber activation, and the release of inflammatory agents, which overall diminishes migraine symptoms (Figure 2 ) [ 19 , 27 , 35 ].…”

“…Ubrogepant is a novel oral medication specifically designed for the acute treatment of migraines [ 18 , 19 ]. It belongs to a class of drugs known as calcitonin gene-related peptide (CGRP) receptor antagonists [ 18 , 20 , 21 ].…”

“…It belongs to a class of drugs known as calcitonin gene-related peptide (CGRP) receptor antagonists [ 18 , 20 , 21 ]. CGRP is a peptide that has been identified as a critical player in the pathophysiology of migraines, and blocking its activity has emerged as a promising strategy for migraine [ 19 , 20 , 22 ].…”

Intracellular pathways of calcitonin gene‐related peptide‐induced relaxation of human coronary arteries: A key role for Gβγ subunit instead of cAMP

“…Novel antimigraine medication aims to block either CGRP or its receptor, using small‐molecule CGRP receptor antagonists (gepants; e.g., atogepant, rimegepant, ubrogepant and zavegepant) or monoclonal antibodies targeting CGRP (eptinezumab, fremanezumab, galcanezumab) or its receptor (erenumab) (de Vries et al, 2020). In human isolated arteries, gepants or the monoclonal antibody erenumab potently block the relaxation to CGRP (de Vries et al, 2023; Rubio‐Beltrán, Labastida‐Ramírez, et al, 2019). However, CGRP (receptor) blockade does not effectively reduce migraine in all patients.…”

“…In human isolated arteries, gepants or the monoclonal antibody erenumab potently block the relaxation to CGRP (de Vries et al, 2023;Rubio-Beltrán, Labastida-Ramírez, et al, 2019). However, CGRP (receptor) blockade does not effectively reduce migraine in all patients.…”