Pharmacological characterization of ubrogepant and atogepant in cAMP assays at human, rat, and mouse calcitonin family receptors in transfected cells

Abstract

Calcitonin gene-related peptide (CGRP) is involved in migraine pathophysiology, and can activate multiple receptors belonging to the calcitonin receptor family; this includes the CGRP receptor, adrenomedullin and amylin (AMY) receptors. Ubrogepant and atogepant, which were designed to target the CGRP receptor, are therapeutically approved for the management of migraine. However, there are limited data on their ability to antagonize members of the wider calcitonin receptor family. We therefore defined the receptor pharmacology of ubrogepant and atogepant at each of the seven calcitonin family receptors from rat, mouse and human. Cos7 cells transiently transfected with each receptor were exposed to species-matched agonists in the absence or presence of ubrogepant and atogepant. As all receptors robustly couple to the G_αs G protein, cyclic adenosine monophosphate production was measured and antagonist potency quantified. Ubrogepant and atogepant antagonized multiple rodent receptors, although the exact profile differed between compound and species. Both compounds were relatively non-selective between rat receptors, suggesting it may be difficult to interpret results in rat models. Selectivity was distinct at mouse receptors. For human receptors, both compounds were most potent at the CGRP receptor, however there was also some affinity at other receptors from this family, especially the AMY₁ receptor. Collectively, our data show that while these compounds are most potent at the CGRP receptor, they have activity at other receptors from the calcitonin receptor family, and this activity differs between species. Our data provide a framework for understanding the activity of ubrogepant and atogepant in rat, mouse and human studies.