Characterization of erenumab and rimegepant on calcitonin gene-related peptide induced responses in Xenopus Laevis oocytes expressing the calcitonin gene-related peptide receptor and the amylin-1 receptor

Background The clinical use of calcitonin gene-related peptide receptor (CGRP-R) antagonists and monoclonal antibodies against CGRP and CGRP-R has offered new treatment possibilities for migraine patients. CGRP activates both the CGRP-R and structurally related amylin 1 receptor (AMY(1)-R). The relative effect of erenumab and the small-molecule CGRP-R antagonist, rimegepant, towards the CGRP-R and AMY-R needs to be further characterized. Methods The effect of CGRP and two CGRP-R antagonists were examined in Xenopus laevis oocytes expressing human CGRP-R, human AMY(1)-R and their subunits. Results CGRP administered to receptor expressing oocytes induced a concentration-dependent increase in current with the order of potency CGRP-R> > AMY(1)-R > calcitonin receptor (CTR). There was no effect on single components of the CGRP-R; calcitonin receptor-like receptor and receptor activity-modifying protein 1. Amylin was only effective on AMY(1)-R and CTR. Inhibition potencies (pIC(50) values) for erenumab on CGRP induced currents were 10.86 and 9.35 for CGRP-R and AMY(1)-R, respectively. Rimegepant inhibited CGRP induced currents with pIC(50) values of 11.30 and 9.91 for CGRP-R and AMY(1)-R, respectively. Conclusion Our results demonstrate that erenumab and rimegepant are potent antagonists of CGRP-R and AMY(1)-R with 32- and 25-times preference for the CGRP-R over the AMY(1)-R, respectively. It is discussed if this difference in affinity between the two receptors is the likely reason why constipation is a common and serious adverse effect during CGRP-R antagonism but less so with CGRP binding antibodies.

Automated summary

The use of new CGRP receptor antagonists and monoclonal antibodies targeting CGRP and CGRP-R has provided new treatment options for migraine patients. The study showed that erenumab and rimegepant are potent antagonists of CGRP-R and AMY(1)-R with significantly higher preference for CGRP-R over AMY(1)-R.