Targeting a family B GPCR/RAMP receptor complex: CGRP receptor antagonists and migraine

Br J Pharmacol. 2012 May;166(1):66-78. doi: 10.1111/j.1476-5381.2011.01633.x.


The clinical effectiveness of antagonizing the calcitonin gene-related peptide (CGRP) receptor for relief of migraine pain has been clearly demonstrated, but the road to the development of these small molecule antagonists has been daunting. The key hurdle that needed to be overcome was the CGRP receptor itself. The vast majority of the current antagonists recognize similar epitopes on the calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 1 (RAMP1). RAMP1 is a relatively small, single, transmembrane-spanning protein and along with the G-protein-coupled receptor CLR comprise a functional CGRP receptor. The tri-helical extracellular domain of RAMP1 plays a key role in the high affinity binding of CGRP receptor antagonists and drives their species-selective pharmacology. Over the years, a significant amount of mutagenesis data has been generated to identify specific amino acids or regions within CLR and RAMP1 that are critical to antagonist binding and has directed attention to the CLR/RAMP1 extracellular domain (ECD) complex. Recently, the crystal structure of the CGRP receptor ECD has been elucidated and not only reinforces the early mutagenesis data, but provides critical insight into the molecular mechanism of CGRP receptor antagonism. This review will highlight the drug design hurdles that must be overcome to meet the desired potency, selectivity and pharmacokinetic profile while retaining drug-like properties. Although the development of these antagonists has proved challenging, blocking the CGRP receptor may one day represent a new way to manage migraine and offer hope to migraine sufferers.

Publication types

  • Review

MeSH terms

  • Animals
  • Calcitonin Gene-Related Peptide Receptor Antagonists*
  • Drug Delivery Systems
  • Drug Design
  • Epitopes
  • Humans
  • Migraine Disorders / drug therapy*
  • Migraine Disorders / physiopathology
  • Protein Binding
  • Protein Conformation
  • Receptor Activity-Modifying Protein 1 / metabolism*
  • Receptors, Calcitonin Gene-Related Peptide / metabolism
  • Species Specificity


  • Calcitonin Gene-Related Peptide Receptor Antagonists
  • Epitopes
  • Receptor Activity-Modifying Protein 1
  • Receptors, Calcitonin Gene-Related Peptide