de Vries Tessa, Boucherie Deirdre M, van den Bogaerdt Antoon, Danser A H Jan, MaassenVanDenBrink Antoinette
Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus MC University Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands.
ETB-BISLIFE, Heart Valve Department, 1940 Beverwijk, The Netherlands.
Pharmaceuticals (Basel). 2023 Jul 28;16(8):1075. doi: 10.3390/ph16081075.
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 pA 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 pA 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.
多种靶向降钙素基因相关肽（CGRP）受体的药物已被开发用于治疗偏头痛。在此，研究了小分子CGRP受体拮抗剂zavegepant（0.1 nM - 1 μM）对离体人冠状动脉（HCA）中CGRP诱导的舒张作用。构建了Schild图并计算了pA值以确定zavegepant的效价。比较了我们早期研究中阿托格潘、奥昔格潘、利美吉泮、替卡格潘、乌布罗格潘和zavegepant在HCA和人脑膜中动脉（HMMA）中的效价和Schild图斜率。Zavegepant使HCA中CGRP的浓度 - 反应曲线发生移位。相应的Schild图斜率与1无差异，得出pA值为9.92±0.24。未观察到HCA和HMMA之间的效价差异。有趣的是，在HCA中Schild图斜率<1的奥昔格潘、阿托格潘和利美吉泮在HMMA中的效价比在HCA中高>1个对数单位，而Schild图斜率与1无差异的替卡格潘、乌布罗格潘和zavegepant在两种组织中的效价相似（<1个对数差异）。由于Schild图斜率<1可能表明涉及多个受体，进一步确定HCA中参与对CGRP舒张反应的受体很重要，这可用于提高未来抗偏头痛药物的心血管安全性。
