CGRP receptor antagonists: toward a novel migraine therapy

Migraine remains one of the most prevalent and disabling neurological disorders that often affects a person during their most productive years. Migraine afflicts approximately 11% of the adult population globally, causes substantial disability, which translates into lost productivity both at home and at work. Clearly there remains a need for new approaches to treat migraine and calcitonin gene-related peptide (CGRP) receptor antagonists have the potential to be a major advance in antimigraine therapy. CGRP was first proposed to play a role in migraine pathophysiology a little over 20 years ago and today there is considerable evidence that CGRP plays a key role in the pathogenesis of migraine. CGRP is a 37 amino acid vasoactive neuropeptide largely expressed in sensory neurons. It was observed that plasma levels of CGRP were elevated during the headache phase of migraine and the levels were normalized concomitantly with pain relief. This observation, along with other evidence, suggested that CGRP receptor antagonists might represent a novel approach to migraine treatment. The advent of small molecule CGRP receptor antagonists has clearly demonstrated a clinical link between blocking the CGRP receptor and effectiveness in treating migraine. This review will highlight the biology of CGRP as it pertains to migraine; discuss the CGRP receptor; spotlight the development of CGRP receptor antagonists; and examine site of action.