CGRP receptor antagonists and antibodies against CGRP and its receptor in migraine treatment

Br J Clin Pharmacol. 2015 Aug;80(2):193-9. doi: 10.1111/bcp.12618. Epub 2015 May 19.


Recently developed calcitonin gene-related peptide (CGRP) receptor antagonistic molecules have shown promising results in clinical trials for acute treatment of migraine attacks. Drugs from the gepant class of CGRP receptor antagonists are effective and do not cause vasoconstriction, one of the major limitations in the use of triptans. However their use had to be discontinued because of risk of liver toxicity after continuous exposure. As an alternative approach to block CGRP transmission, fully humanized monoclonal antibodies towards CGRP and the CGRP receptor have been developed for treatment of chronic migraine (attacks >15 days/month). Initial results from phase I and II clinical trials have revealed promising results with minimal side effects and significant relief from chronic migraine as compared with placebo. The effectiveness of these various molecules raises the question of where is the target site(s) for antimigraine action. The gepants are small molecules that can partially pass the blood-brain barrier (BBB) and therefore, might have effects in the CNS. However, antibodies are large molecules and have limited possibility to pass the BBB, thus effectively excluding them from having a major site of action within the CNS. It is suggested that the antimigraine site should reside in areas not limited by the BBB such as intra- and extracranial vessels, dural mast cells and the trigeminal system. In order to clarify this topic and surrounding questions, it is important to understand the localization of CGRP and the CGRP receptor components in these possible sites of migraine-related regions and their relation to the BBB.

Keywords: BBB; CGRP; CGRP receptor; CLR; gepants; monoclonal antibodies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics / administration & dosage
  • Analgesics / pharmacokinetics
  • Analgesics / therapeutic use*
  • Antibodies, Monoclonal, Humanized / administration & dosage
  • Antibodies, Monoclonal, Humanized / pharmacokinetics
  • Antibodies, Monoclonal, Humanized / therapeutic use*
  • Blood-Brain Barrier / metabolism*
  • Calcitonin Gene-Related Peptide / antagonists & inhibitors*
  • Calcitonin Gene-Related Peptide Receptor Antagonists*
  • Clinical Trials as Topic
  • Humans
  • Migraine Disorders / drug therapy*
  • Migraine Disorders / metabolism
  • Trigeminal Ganglion / metabolism*


  • Analgesics
  • Antibodies, Monoclonal, Humanized
  • Calcitonin Gene-Related Peptide Receptor Antagonists
  • Calcitonin Gene-Related Peptide