Calcitonin Gene-Related Peptide (CGRP)
/ Endogenous 37-residue calcitonin gene-related peptide; CGRP receptor (CALCRL/RAMP1) agonistALIAS · Calcitonin gene-related peptide · alpha-CGRP · CGRP-alpha
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Tier 1 for the CGRP pathway. Native CGRP itself is not a therapeutic, but the CGRP signalling axis is one of the most successfully drugged in modern neurology: anti-CGRP monoclonal antibodies (erenumab, fremanezumab, galcanezumab, eptinezumab) and small-molecule CGRP-receptor antagonists (rimegepant, ubrogepant, atogepant, zavegepant) are FDA-approved for migraine prevention and / or acute treatment.
CGRP is a 37-residue peptide produced by alternative splicing of the calcitonin (CALCA) gene; the alpha-CGRP isoform is the predominant neuronal form, with beta-CGRP encoded by a separate adjacent gene (CALCB). The peptide contains an N-terminal disulfide loop and a C-terminal amide, both required for full receptor engagement.
The canonical CGRP receptor is a heterodimer of the calcitonin receptor-like receptor (CALCRL / CLR) with receptor activity-modifying protein 1 (RAMP1); a third component, receptor component protein (RCP), supports Gs coupling. The receptor is widely expressed in vascular smooth muscle, trigeminal nerve fibres, the trigeminal ganglion, and central CNS nuclei involved in pain processing. Activation drives potent vasodilation and modulates nociceptive transmission.
In migraine pathophysiology, trigeminal-vascular release of CGRP at meningeal vessels and at the trigeminal ganglion is a central event - elevated CGRP is detectable in jugular venous blood during migraine attacks, intravenous CGRP triggers migraine-like headache in migraineurs, and blockade of CGRP or its receptor produces the therapeutic effect of the gepant and anti-CGRP antibody classes.
Tier 1 for the CGRP-blocking drug class. Anti-CGRP monoclonals (erenumab targeting the CGRP receptor; fremanezumab, galcanezumab, and eptinezumab targeting the ligand) are FDA-approved for migraine prevention based on multiple Phase 3 RCTs. Small-molecule CGRP-receptor antagonists - rimegepant (acute and prevention), ubrogepant (acute), atogepant (prevention), zavegepant (intranasal acute) - are FDA-approved for acute and / or preventive migraine indications. Native CGRP itself remains a non-therapeutic experimental probe.
The CGRP-blocking drug class has a generally favourable safety profile in pivotal trials - common adverse effects are injection-site reactions (monoclonals), constipation (notably with erenumab), and modest blood-pressure elevation (post-marketing signal for erenumab). Long-term cardiovascular outcome data are accumulating; the theoretical concern that chronic CGRP blockade could affect cardiovascular reserve in ischemic conditions has not been borne out at scale to date but remains under surveillance.
Regulatory status
- FDA status:
- FDA-approved
The native peptide itself has no therapeutic indication and is not interchangeable with the approved CGRP-blocking agents - vendors selling 'CGRP peptide' material are supplying a research reagent, not a migraine therapeutic.
Within the approved class, head-to-head comparative effectiveness across the four monoclonals and the gepants is limited; payer-driven sequencing decisions often outweigh evidence-based selection. Pregnancy and lactation safety data remain limited.