AM833 is a novel agonist of calcitonin family G protein-coupled receptors: pharmacological comparison to six selective and non-selective agonists

Obesity and associated co-morbidities are a major health burden and novel therapeutics to help treat obesity are urgently needed. There is increasing evidence that targeting the amylin receptors (AMYRs), heterodimers of the calcitonin G protein-coupled receptor (CTR) and receptor activity-modifying proteins (RAMPs), improves weight control, and has the potential to act additively with other treatments such as glucagon-like peptide-1 receptor agonists. Recent data indicates that AMYR agonists, which can also independently activate the CTR, may have improved efficacy for treating obesity, even though selective activation of CTRs is not efficacious. AM833 (cagrilintide) is a novel, lipidated, amylin analogue that is undergoing clinical trials as a non-selective AMYR and CTR agonist. In the current study, we have investigated the pharmacology of AM833 across 25 end points and compared this peptide with AMYR selective and non-selective lipidated analogues; AM1213 and AM1784, and the clinically used peptide agonists; pramlintide (AMYR selective), sCT (non-selective). We also profiled hCT and rat amylin as prototypical selective agonists of CTR and AMYRs, respectively. Our results demonstrate that AM833 has a unique pharmacological profile, across diverse measures of receptor binding, activation and regulation. Significance Statement AM833 is a novel non-selective agonist of calcitonin-family receptors that has demonstrated efficacy for the treatment of obesity in phase 2 clinical trials. In this study we demonstrate that AM833 has a unique pharmacological profile across diverse measures of receptor binding, activation and regulation, when compared to other selective and non-selective calcitonin receptor and amylin receptor agonists. Our data provide mechanistic insight into the actions of AM833.