Ubrogepant

Calcitonin gene-related peptide (CGRP) is a 37 amino acid neuropeptide released from the cell bodies and axonal terminals of trigeminal sensory nerves. In physiological states, CGRP is known to play a role in maintaining tissue homeostasis and vascular tone, but during migraine, increased release of CGRP has been shown. The signaling cascade that follows CGRP binding results in the opening of potassium channels, an increase in cyclic AMP, and causes powerful and immediate vasodilation of meningeal and cerebral vessels. In addition, CGRP sensitizes perivascular nociceptors, leads to extravasation of plasma proteins, and enhances central transmission of nociceptive information to brainstem and thalamus.
Ubrogepant is a small-molecule CGRP receptor antagonist designed rationally and exhibits no intrinsic agonist activity. Upon oral administration, Ubrogepant is widely distributed to peripheral and central tissue compartments where it displaces CGRP from the orthosteric binding site on CLR/RAMP1. Binding of Ubrogepant to the CGRP receptor physically occludes the peptide and inhibits the peptide-initiated signaling cascade. In the spinal trigeminal nucleus and other higher-order pain pathways, antagonism of CGRP receptors dampens CGRP-induced enhancement of glutamate release and neuronal hyperexcitability thereby breaking the cycle of self-perpetuating headaches and associated features such as photophobia and nausea. As Ubrogepant acts via non-vasoconstrictive antagonism rather than serotonergic vasoconstriction, it may provide migraine relief without the vascular safety concerns seen with triptans.

Fig. 1 Ubrogepant blocks CGRP for migraine treatment. (Russo A F.; et al. 2023)