Rimegepant

Rimegepant is a small-molecule CGRP receptor antagonist that blocks the end-stage of the migraine pain pathway. Activation of trigeminal afferents trigger exocytosis of CGRP from dense-core vesicles onto Aδ-fibres and intracranial vessels. CGRP then binds a heteromeric CLR/RAMP1 receptor to couple Gs, increasing cAMP and driving vasodilation, plasma-protein extravasation and sensitisation of perivascular nerves. Rimegepant fits into the hydrophobic cavity created by CLR/RAMP1 to reversibly occupy the binding site, thereby acting as a molecular blockade that precludes CGRP from docking and silences subsequent signal transduction without causing vasoconstriction.
Because Rimegepant neither constricts coronary nor cerebral vessels, it can be used in patients with ischaemic heart disease, uncontrolled hypertension or previous intolerance to triptans; also due to its lack of serotonergic activity, medication-overuse headaches are not caused even with frequent use. The tablet can be dissolved on the tongue within seconds. It gives peak concentrations in about 90 minutes and has an elimination half-life of approximately 11 hours, which is long enough to provide sustained benefit and short enough to allow for rapid clearance in the event of an adverse event.

Fig. 1 Mechanism of action of Rimegepant in migraine treatment. (Edvinsson L.; et al. 2024)