Cagrilintide (AM833) has a unique pharmacological profile as a nonselective agonist of both amylin and calcitonin receptors, distinguishing it from pramlintide and other peptide agonists across 25 different measures.
25 endpoints profiledCagrilintide showed a distinct pharmacological fingerprint across 25 measures of receptor binding, activation, and regulation versus 5 other peptide agonists
What the researchers found
AM833 (cagrilintide) is a nonselective agonist with a unique pharmacological profile across 25 endpoints of receptor binding, activation, and regulation compared to 5 other selective and nonselective AMYR/CTR agonists including pramlintide and salmon calcitonin.
Why it matters
Understanding why cagrilintide works better than selective agonists helps optimize next-generation obesity drugs. The nonselective receptor profile explains its additive effects when combined with GLP-1 drugs like semaglutide (CagriSema).
The numbers in context
25 endpoints; 7 peptides compared; AM833 nonselective at AMYR + CTR; unique profile vs pramlintide (selective), salmon CT (nonselective), and 4 others
How the study worked
In vitro pharmacological profiling. AM833 compared against AM1213, AM1784, pramlintide, salmon calcitonin, human calcitonin, and rat amylin across 25 endpoints measuring receptor binding, signaling activation, and receptor regulation at calcitonin and amylin receptor subtypes.
Who was studied
In vitro receptor pharmacology across calcitonin family receptors
What this study cannot tell us
In vitro receptor pharmacology study — does not directly measure weight loss or clinical outcomes. Receptor-level activity may not fully predict in vivo efficacy. Differences between cell-based assays and physiological conditions are possible.
How to read the evidence
Moderate evidence: comprehensive in vitro pharmacological characterization supporting clinical findings, but receptor-level data does not directly predict therapeutic outcomes.
When this study was published
Published 2021. Cagrilintide has since advanced to Phase 3 clinical trials in combination with semaglutide (CagriSema) for obesity.
The bigger picture
Cagrilintide represents the evolution from pramlintide (a selective amylin receptor agonist with modest effects) to a nonselective dual-receptor agonist with substantially greater weight loss potential. Understanding this pharmacology guides the design of future obesity peptide drugs.
Questions still open
- Does the dual CTR/AMYR activation explain cagrilintide's additive effects with semaglutide?
- Could the receptor regulation profile predict which patients respond best to cagrilintide?
- Can the pharmacological insights from this study guide design of even more effective amylin analogues?
Common questions
What makes cagrilintide different from pramlintide?
Why does activating multiple receptors matter for weight loss?
Read the original research
AM833 Is a Novel Agonist of Calcitonin Family G Protein-Coupled Receptors: Pharmacological Comparison with Six Selective and Nonselective Agonists.
The Journal of pharmacology and experimental therapeutics, 377(3), 417-440
Citation
Fletcher, Madeleine M; Keov, Peter; Truong, Tin T; Mennen, Grace; Hick, Caroline A; Zhao, Peishen; Furness, Sebastian G B; Kruse, Thomas; Clausen, Trine R; Wootten, Denise; Sexton, Patrick M. (2021). AM833 Is a Novel Agonist of Calcitonin Family G Protein-Coupled Receptors: Pharmacological Comparison with Six Selective and Nonselective Agonists.. The Journal of pharmacology and experimental therapeutics, 377(3), 417-440. https://doi.org/10.1124/jpet.121.000567