Debbie Hay (Dunedin, NZ), Mhairi Nimick (Dunedin, NZ), Michael Garelja (Dunedin, NZ), Tyla Alexander (Dunedin, NZ), Christopher Walker (Auckland, NZ), Pradeep Banerjee (Chicago, IL, US)
Ubrogepant and atogepant belong to the "gepant" class of CGRP receptor antagonists. There are limited data on their ability to antagonize different members of the wider calcitonin receptor family. This study aimed to address this by comparing antagonism by ubrogepant and atogepant at the CGRP, calcitonin, adrenomedullin, and amylin receptors from three species.
Cos7 cells transiently transfected with human, rat or mouse receptor subunits for all seven calcitonin family receptors were exposed to species-matched agonists in the absence or presence of ubrogepant and atogepant. Two other gepants (rimegepant and telcagepant) were also studied as comparators in some experiments. As all of these receptors robustly couple to the Gαs G protein, cAMP production was quantified and antagonist potency calculated.
Ubrogepant and atogepant were antagonists of the human CGRP receptor and were also able to antagonize the AMY1(a) receptor. Selectivity estimates between these two human receptors varied depending on assay format and agonist used. As an example of the results, Table 1 shows IC50 values at the human CGRP and AMY1(a) receptors. Antagonism was weaker at mouse and rat receptors, compared to human. Depending on the species, antagonism of other receptors was sometimes observed. Overall, there were some differences in selectivity between receptors in the different species.
Ubrogepant and atogepant are capable of antagonizing additional receptors in the calcitonin receptor family, beyond the canonical CGRP receptor.