Cagrilintide: Structure, Receptor Pharmacology and Chemistry

Cagrilintide is a synthetic analogue of human amylin, a 37-residue pancreatic peptide hormone. It was developed by Kruse and colleagues as compound 23 in a medicinal-chemistry series published in 2021, selected as a stable, lipidated, long-acting analogue. The design problem their paper describes is specific: native human amylin has a high propensity toward amyloid fibril formation, which makes it difficult to work with as a stable molecule.

The molecule sits on the pramlintide backbone, which carries proline substitutions at positions 25, 28 and 29. Cagrilintide adds further changes, and the structural literature is explicit about their purpose. Cao and colleagues state that a pair of helix-stabilizing substitutions, N14E and V17R, were incorporated specifically to counteract the amyloid fibril formation seen with human amylin. Position 37 carries proline in place of the tyrosine found in rat amylin.

The other defining structural feature is lipidation. The peptide is acylated at its N-terminus with a gamma-glutamate linker connected to a C20 fatty diacid. Fatty-acid conjugation of this kind is a well-established approach to extending circulating half-life through albumin association, and it is the feature that distinguishes cagrilintide from shorter-acting amylin analogues.

Cagrilintide is a non-selective agonist across the calcitonin receptor family. That family comprises the calcitonin receptor itself and the three amylin receptors, which are not separate gene products but heterodimers formed when the calcitonin receptor associates with one of three receptor activity-modifying proteins, RAMP1, RAMP2 or RAMP3, yielding AMY1R, AMY2R and AMY3R respectively.

Fletcher and colleagues profiled the pharmacology across 25 endpoints spanning receptor binding, activation and regulation, comparing cagrilintide against rat amylin, human calcitonin, salmon calcitonin, pramlintide and two other lipidated analogues. Their published conclusion was that the compound has a unique pharmacological profile across those diverse measures relative to every comparator tested, and their significance statement describes it as a novel non-selective agonist of calcitonin family receptors.

Because it engages both receptor classes, the compound is also classified in the literature as a dual amylin and calcitonin receptor agonist. Comparative work has shown that different molecules in this class differ in their balance between the two receptor types, meaning receptor selectivity ratio is itself a measurable property that distinguishes analogues rather than a fixed class characteristic.

Two later papers refine that picture from opposite directions. Gostynska and colleagues reported in 2025 that the calcitonin receptor and the RAMP subunits sit in a measurable association equilibrium rather than existing as fixed heterodimers, that peptide agonists shift that equilibrium, and that the shift tracks with the extent of downstream cAMP signalling. Their result reframes the amylin receptors as assemblies whose composition is itself ligand-sensitive.

From the selectivity side, the 2025 discovery report on eloralintide sharpened the contrast. In cell-based assays that molecule preferentially activated the human AMY1 receptor, reported as 12-fold over the calcitonin receptor and 11-fold over AMY3R, and the same paper refers to cagrilintide as a non-selective amylin receptor agonist. Placing a selective analogue beside a non-selective one puts a number on how wide the selectivity range within this class actually is.

Cao and colleagues determined structures of cagrilintide bound to active, Gs-coupled receptor complexes at four receptors: the calcitonin receptor at 2.2 angstrom resolution, AMY1R at 2.2 angstroms, AMY2R at 2.7 angstroms and AMY3R at 3.0 angstroms. The peptide adopts an amylin-like binding mode but induces conformational dynamics at these receptors that differ from other peptides in the family.

Three specific structural findings are worth recording. First, an intramolecular salt bridge between glutamate 14 and arginine 17, the residues introduced by the helix-stabilizing substitutions, stabilizes the N-terminal alpha-helix. Second, residues 19 through 25 adopt what the authors term a bypass conformation, and at the calcitonin receptor roughly 85 percent of imaged particles were stabilized in that conformation versus about 8 percent in a calcitonin-like conformation. Third, proline 37 occupies the same extracellular-domain pocket that tyrosine 37 of rat amylin occupies, but makes no direct contacts with RAMP1 or RAMP3, whereas the bulkier tyrosine of rat amylin does form interactions with RAMP2 residues.

Density for the conjugated lipid was limited in the maps, so modelling was restricted to the gamma-glutamate linker and a short adjacent segment of the fatty diacid. A separate control is informative here: a non-lipidated version of the peptide showed similar potency and maximal response in cells co-expressing the calcitonin receptor with RAMP3, indicating the lipid contributes to circulating persistence rather than to receptor engagement itself.

An independent 2026 cryo-EM study by Gu and colleagues reached consistent conclusions, describing the same bypass binding mode across both receptor classes, identifying phenylalanine 23 and proline 37 as stabilizing peptide positioning, and confirming the E14-R17 salt bridge as a contributor to helical stability.

Beyond static structures, the 2025 work applied three-dimensional variability analysis to the cryo-EM particle sets and molecular dynamics simulation to the complexes. Both approaches converged on the same observation: complexes with cagrilintide showed greater extracellular conformational motion than the equivalent complexes with rat amylin.

The measured motion is substantial for a receptor extracellular domain. RAMP3 extracellular-domain movement of approximately 7 angstroms was reported at the alpha-carbon of glutamate 123. Six microseconds of molecular dynamics simulation comparing cagrilintide and rat amylin at the AMY3R complex reproduced the greater extracellular-domain motion seen in the experimental data.

A 2026 study by Fairweather and colleagues approached receptor dynamics from the ligand-free side using hydrogen-deuterium exchange mass spectrometry, mapping the conformational flexibility of the calcitonin receptor on its own and paired with each of the three RAMPs. The three RAMPs were reported to influence the flexibility of the receptor extracellular domain, the transmembrane helices and the intracellular regions involved in G protein engagement to different extents, with each RAMP showing its own dynamic signature in its transmembrane and C-terminal regions. That work supplies a ligand-free baseline against which the agonist-bound motion described above can be read.

Coordinates and maps from that work are publicly deposited, which makes the findings independently examinable. Structures are available in the Protein Data Bank under accession codes including 9BP3, 9BLW, 9BQ3 and 9BTW, with corresponding density maps in the Electron Microscopy Data Bank.

Two identity issues matter when sourcing or documenting this compound. The first is salt form. The free peptide and the acetate salt are separate chemical entities with separate PubChem records, CID 171397054 and CID 164618153 respectively, and the free peptide CAS number 1415456-99-3 does not describe the acetate. Documentation should specify which form the material is.

The second is naming. The compound appears in the literature under at least four designations: cagrilintide, AM833, NN0174-0833, and as compound 23 in its originating medicinal-chemistry paper. A literature search on the common name alone will miss the discovery and pharmacology work published under the development codes.

On solubility, supplier specifications describe the acetate as slightly soluble in DMSO at 0.1 to 1 mg/mL and sparingly soluble in phosphate-buffered saline at pH 7.2 at 1 to 10 mg/mL, with one supplier listing 10 millimolar in DMSO. These are supplier specifications rather than published measurements. The computed descriptors, an XLogP of minus 12.5 and a topological polar surface area of 1880 square angstroms, are consistent with a highly polar lipopeptide.

A third consideration is analytical. Alhalabi and colleagues published in 2026 what they describe as the first systematic in vitro metabolic profiling of this molecule alongside pramlintide and KBP-066, using human skin S9 fraction, kidney S9 fraction and biological fluids, and cross-checking the predicted products against authentic rat samples. All three peptides underwent N-terminal and C-terminal degradation to multiple stable products, and validated LC-MS/MS methods were established for those products. For anyone documenting material identity or tracking degradation, that paper is the first published set of characteristic fragments for the compound.

Storage and solubility figures for this compound come from supplier specifications rather than from peer-reviewed measurement. Suppliers specify storage of the solid at minus 20 degrees Celsius, with one listing 12 months at that temperature or 6 months at 4 degrees Celsius for the powder, and 6 months at minus 80 or minus 20 degrees Celsius in solvent. Solubility is described as 0.1 to 1 mg/mL in DMSO and 1 to 10 mg/mL in phosphate-buffered saline at pH 7.2.

One property of the parent hormone is directly relevant to laboratory work with any amylin analogue. Native human amylin aggregates readily into amyloid fibrils, which is the stability problem the whole analogue series was designed around. The N14E and V17R substitutions in this molecule were introduced specifically to stabilize the helix against that behavior, so the analogue is expected to be more tractable in solution than the native hormone.

For researchers working on mode of action, one practical note appears in the literature itself: a dedicated rodent tool compound sharing 95 percent sequence homology and an identical acylation sidechain was developed and described in 2025, because availability of cagrilintide for research is restricted under pharmacovigilance rules. Gabery and colleagues designate that tool compound 0839 and cagrilintide itself 0833, and state that 0839 is obtainable through the originator's compound-sharing program.