Decoding Amylin Receptor Architecture, Ligand Engagement & Signaling

This workshop addresses the field’s most pressing challenge: determining optimal receptor targeting strategies. The session will explore the complex receptor system (amylin I, II, III, and calcitonin receptors), examining the debate between amylin selective versus dual amylin-calcitonin receptor agonist (DACRA) approaches. Participants will analyze preclinical data from rats suggesting amylin III importance versus emerging human data showing different profiles, discuss the lack of translatable antibodies to RAMPs limiting receptor distribution mapping, and evaluate signaling bias (beta-arrestin vs G-protein pathways) and its impact on efficacy and tolerability. 

What attendees will gain:

Attendees will leave with a framework for evaluating receptor selectivity strategies, understanding the trade-offs between precision targeting and broad receptor coverage, and insights into how receptor profiles may predict clinical outcomes.

Key questions to be addressed:

• Which amylin receptor subtype (I, II, or III) is most critical for weight loss efficacy in humans, and how does this differ from rodent models?
• Should next-generation therapeutics target amylin receptors selectively or employ a DACRA approach, and what are the mechanistic rationales for each strategy?
• How does signaling bias (beta-arrestin vs G-protein recruitment) influence tolerability, efficacy, and quality of weight loss?
• What tools and methodologies are needed to definitively map receptor distribution in human brain and peripheral tissues?
• How can we overcome the species translation challenge when rodent receptor profiles don’t match human profiles?