Alpha-CGRP: natural migraine and pain-signalling peptide
A natural peptide made by nerve cells that widens blood vessels and transmits pain signals; blocking it is the basis of several approved migraine drugs.
- Class
- Endogenous neuropeptide / vasodilatory peptide (canine ortholog)
- Status
- No approved therapeutic status identified
- Main caveat
- Canine (dog) form of alpha-CGRP. Source provides sequence and chromosomal gene assignment only. No in vitro, animal efficacy, or human evidence attached to this card's source file.
A researcher, an agent, or an algorithm wrote down the sequence and picked a target to hit.
An AI model like OpenFold3 or AlphaFold built a 3D structure and scored how well it fits the binding site.
A second contributor repeated the computation on their own hardware and the scores matched.
A chemistry service or a researcher ordered the sequence, it was manufactured, and mass spectrometry confirmed the right molecule was produced.
A binding or activity measurement confirmed that it actually does what the computer predicted — or didn't.
What this is
Alpha-calcitonin gene-related peptide (α-CGRP) is a 37-amino acid signalling peptide produced naturally in the human body, primarily by sensory neurons and the central nervous system. It belongs to the calcitonin/CGRP peptide family — a group that includes calcitonin, amylin, and adrenomedullin — all of which signal through a shared set of receptors (Hay and colleagues, British Journal of Pharmacology, 2018). α-CGRP is one of the most potent vasodilators known and plays a central role in pain transmission; it has become a major pharmacological target for migraine therapy. The stored 37-residue sequence represents the bare backbone; the active peptide carries a disulfide bond between the cysteine residues at positions 2 and 7, forming an N-terminal ring, and a C-terminal amide — neither feature is visible in the raw sequence shown here.
History
The α-CGRP gene (CALC-I) was identified from the calcitonin gene in the early 1980s as an alternative splicing product; the same gene encodes calcitonin in thyroid C-cells and α-CGRP in neuronal tissue depending on which exon is included. The chromosomal assignment and molecular structure of the canine CALC-I/α-CGRP gene were reported by Wende and colleagues (Mammalian Genome, 2000), providing comparative genomic context for the human locus. The receptor pharmacology of the whole calcitonin/CGRP family was substantially clarified over the subsequent two decades, culminating in a comprehensive IUPHAR review by Hay and colleagues (British Journal of Pharmacology, 2018) that codified the receptor nomenclature: the CGRP receptor is formed by the calcitonin receptor-like receptor (CLR) paired with receptor activity-modifying protein 1 (RAMP1), while the amylin receptors (AMY₁, AMY₂, AMY₃) are formed by the calcitonin receptor (CTR) paired with RAMP1, RAMP2, or RAMP3.
What it does
α-CGRP acts primarily through the CGRP receptor (CLR/RAMP1) to produce potent vasodilation throughout the cardiovascular system and modulates pain signals at both peripheral sensory neurons and in the spinal cord. Its vasodilatory action makes it a key player in the dilation of cranial blood vessels during migraine attacks, which is why blocking α-CGRP signalling — either with monoclonal antibodies against the peptide itself or against its receptor — has become a validated strategy for migraine prevention. Beyond migraine, α-CGRP has reported roles in bone metabolism, cardiovascular regulation, and wound healing. Its receptor-binding pharmacology overlaps with other calcitonin-family members: at high concentrations, α-CGRP can also activate amylin receptors (CTR/RAMP complexes), as characterised by Lee and colleagues (Journal of Biological Chemistry, 2016).
Evidence
- Human: α-CGRP is the pharmacological target — not the drug — in the approved class of CGRP-pathway migraine therapies. Clinical evidence for CGRP receptor blockade in migraine prevention is extensive at the Phase III level; this card covers the endogenous peptide itself rather than the anti-CGRP biologics. No clinical trials of exogenous α-CGRP administration as a therapeutic are present in the dossier.
- Animal: Extensive preclinical characterisation across rodent and other models for vasodilation, nociception, and bone physiology; receptor binding and signalling studies establish the CLR/RAMP1 pharmacology (Barwell and colleagues, British Journal of Pharmacology, 2012).
- In vitro: Receptor interaction mechanisms between α-CGRP and calcitonin/amylin receptor systems have been characterised at the molecular level (Lee and colleagues, Journal of Biological Chemistry, 2016). Expression studies of CTR, CLR, and RAMP1–3 during osteoclast differentiation have been conducted in mouse bone marrow macrophage models (Granholm and colleagues, Journal of Cellular Biochemistry, 2008).
Known effects
- Vasodilation — Potent endogenous effect at CLR/RAMP1; well-established in preclinical and human physiology.
- Modulation of pain/nociception — Preclinical and pharmacological evidence; central to the migraine mechanism.
- Bone metabolism — Preclinical; CTR and CLR are both expressed in osteoclast lineage cells (Granholm and colleagues, 2008); calcitonin family signalling influences bone resorption (Pondel, International Journal of Experimental Pathology, 2000; Davey and colleagues, Journal of Bone and Mineral Research, 2013).
- Cardiovascular regulation — Endogenous role supported by the broad vascular distribution of CGRP receptors; documented in the IUPHAR pharmacology review (Hay and colleagues, 2018).
Mechanism
α-CGRP binds preferentially to the CGRP receptor, a heterodimeric Class B (secretin-family) GPCR consisting of CLR paired with RAMP1. RAMP1 is essential for surface expression of CLR and determines its ligand selectivity toward CGRP over adrenomedullin (Hay and colleagues, 2018). Receptor activation couples primarily through Gαs, stimulating cAMP production and downstream vasodilation and nociceptive signalling. At the amylin receptors (CTR/RAMP1, CTR/RAMP2, CTR/RAMP3), α-CGRP also has agonist activity, though with lower potency than at CLR/RAMP1; the molecular basis of cross-reactivity between CGRP, amylin, and calcitonin across this receptor family was reviewed by Barwell and colleagues (2012) and by Lee and colleagues (2016). The calcitonin receptor itself (CTR, the primary target for calcitonin and amylin) shares Class B GPCR architecture with CLR; both signal through multiple G-protein pathways and interact with RAMPs to diversify their pharmacology.
Related peptides
- Calcitonin — the other major product of the CALC-I gene; expressed in thyroid C-cells rather than neurons; acts primarily at CTR to regulate bone resorption and calcium homeostasis.
- Amylin (islet amyloid polypeptide, IAPP) — co-secreted with insulin from pancreatic β-cells; signals through CTR/RAMP complexes (AMY₁–₃); shares partial sequence homology with α-CGRP and cross-reacts at CGRP receptors (Hay and colleagues, 2018).
- Adrenomedullin — another calcitonin-family member acting via CLR/RAMP2 (AM₁ receptor) and CLR/RAMP3 (AM₂ receptor); potent vasodilator with roles in cardiovascular and lymphatic physiology.
Research directions for this peptide, selected from the current sources — hypotheses you can explore and model. None of it is proven yet; tap any one to see the full thinking.
Could the pain-signalling peptide CGRP act directly on bone cells to reduce the bone loss that occurs during breastfeeding?
If true, a new approach to preventing osteoporosis in new mothers could be developed by boosting or mimicking this natural peptide signal, helping reduce fragility fractures in postpartum women.
Could replacing just two amino acids in human alpha-CGRP, guided by the equine sequence, produce a version that targets pain receptors without activating metabolic receptors?
If confirmed, this could lead to sharper migraine treatments that avoid the metabolic side effects of current CGRP-family drugs, potentially making them safer for long-term use in patients with diabetes or metabolic conditions.
▸full evidence table2 metrics
| metric | value | tool |
|---|---|---|
| ipTM | 0.8233843445777893 | openfold3-mlx |
| ranking score | 0.9092643857002258 | openfold3-mlx |
▸structural qualityopenfold3
| metric | value | note |
|---|---|---|
| gpde | 0.777 | global PDE — lower = better |
| disorder | 0.209 | fraction disordered |
| chain pair ipTM (A, B) | 0.823 | interface quality |
▸3-letter notation
▸recipeopenfold3-mlx 0.3.1
| parameter | value |
|---|---|
| model | openfold3-mlx 0.3.1 |
| weights | aedd8f3eb814e392… |
| hardware | apple_m4_base_16gb |
| mlx version | 0.31.1 |
| python | 3.14.3 |
| random seed | 42 |
| msa strategy | colabfold |
| diffusion samples | 1 |
| runtime | 463s |
| predicted by | mlx@peptide |
| predicted at | 2026-04-24 |
python3 openfold3/run_openfold.py predict --query_json {query.json} --runner_yaml examples/example_runner_yamls/mlx_runner.yml --output_dir {output_dir} --num_diffusion_samples 1 ▸citationbibtex
@peptide{pep10645,
sequence = {SCNTATCVTHRLAGLLSRSGGVVKNNFVPTNVGSEAF},
target = {calcr},
author = {peptidemodel},
year = {2026},
status = {synthesized}
}