Cagriniltide: Mechanism of Action

Mechanism of Action

Cagriniltide functions as a non-selective dual agonist of both calcitonin receptors (CTR) and amylin receptors (AMY1R, AMY2R, AMY3R) — heterodimers of CTR with RAMPs 1, 2, or 3.[3][12]

Receptor Targets & Binding

Target	Interaction	Evidence
Calcitonin Receptor (CTR)	Non-selective agonist; class B1 GPCR; EC50 62 pM	Kruse et al. (2021); Cao et al. (2025) cryo-EM[3][9]
AMY1R (CTR+RAMP1)	Potent agonist; "bypass" conformation binding	RAMP1/3 KO abolishes weight-loss effects[8]
AMY3R (CTR+RAMP3)	Potent agonist; EC50 49 pM (hAMY3R)	Carvas et al. (2025): essential for efficacy[8][13]
CGRPR / AM1R / AM2R	No or very low activity — selective for amylin/calcitonin axis	Fletcher et al. (2021)[12]

Downstream Signaling

Pathway	Effect	Consequence
Gs / Adenylyl Cyclase / cAMP	Gs-protein activation → adenylyl cyclase → intracellular cAMP accumulation	Primary signaling cascade for satiety[9]
Neuronal cFos (AP/NTS/LPBN)	Induces cFos expression in area postrema, nucleus of solitary tract, lateral parabrachial nucleus	Satiety signaling; 57% fewer AP neurons in RAMP1/3 KO[8]
Gastric Emptying	Delays gastric emptying → prolonged postprandial fullness	Reduced caloric intake; may affect oral drug absorption
Glucagon Suppression	Suppresses postprandial glucagon from pancreatic α-cells	Improved glycemic control without hypoglycemia risk[6]

Unique Binding Characteristics

Property	Cagriniltide	Salmon Calcitonin
Receptor Conformation	"Bypass" (stabilized by ionic lock N14E–V17R)	"CT-like" conformation
Residence Time	3–6 minutes (rapid dissociation)	45–60 minutes (slow dissociation)
Desensitization	Prevents receptor downregulation → sustained weight loss	Causes receptor downregulation → weight regain

RAMP Dependence: Carvas et al. (2025) demonstrated that the weight-lowering and anorectic effects of cagriniltide are strictly dependent on AMY1R and AMY3R — knockout of RAMP1 and RAMP3 completely abolished drug efficacy, with 57% fewer neurons activated in the area postrema.[8]