Targeting Calcitonin Gene-Related Peptide and its Receptor by Monoclonal Antibody, New Developments in the Prevention of Migraine

Abstract

CitationMigraine is a chronic headache disorder with an unknown pathophysiology. Research in the past decade has shown that to be a brain disorder, a dismodulation of sensory processing affecting vascular tone and pain 1-3 but since the exact pathomechanism of migraine is not very well known, its treatment is also difficult. Current drugs recommended by the "European Federation of Neurological Societies (EFNS)" used in the treatment of migraine include the triptan family drugs that are serotonin (5-HT 1B/D ) receptor agonists, and the Non-Steroid Anti-Inflammatory Drugs (NSAIDs). 4 Several other drugs such as anti-epileptic drugs, beta-blockers, and calcium channel blockers are also recommended in the treatment of migraine. 4 Although glutamic acid is one of the main neurotransmitters in the sensory system, various neuropeptides have been implicated in pain but among them, Calcitonin Gene Related Peptide (CGRP) is the only one neuropeptide that was found elevated in the blood of migraine patients 5-7 and CGRP administration induces migraine-like attack in migraine patients. 8 Therefore, several studies in the last decade focused on drugs to block the CGRP receptor 9-11 or the effect of CGRP itself by antibodies against it 10-12 although, it is not clear if the site of action of these drugs is peripheral or central. 13 Nevertheless, triptan family drugs are currently some of the best and most potent compounds in the treatment of migraine, 4,14 but not all patients respond to them and search for other drugs that lack vasoconstrictive activity has continued. The discovery of CGRP-receptor antagonist drugs, 15 the so called "gepant family drugs" such as telcegepant and olcegepant, and BI 44370 TA were the main events in migraine research in the last decade. [16][17][18][19][20][21] Unfortunately, these drugs were discontinued due to their side effects such as hepatotoxicity although they were able to treat migraine effectively. Nevertheless, some newer drugs in this category including MK-3207, 22,23 BMS-846372 24,25 and MK-1602 26 are still under investigation, see 10 for a brief review. Nevertheless, research in the treatment of migraine did not stop here and search for other drugs being able to block CGRP or its receptor continued.CGRP receptor is a hetero-oligomeric complex that has a peculiar structure and consists of a component, called the "Calcitonin receptor-like receptor (CLR)" which is a transmembrane Gs protein-coupled receptor, and an accessory protein component known as the "Receptor Activity-Modifying Protein 1 (RAMP1)" for the transport of CLR to the plasma membrane, and another component known as "Receptor Component Protein (RCP)" that is important for signaling pathway by determining the G-protein to which the receptor should be coupled with. 10,27,28 In recent years, monoclonal Antibodies (mAbs) against CGRP or its receptor have been developed and are the newest anti-migraine drugs in clinical trials.