University of Oklahoma researchers have achieved a significant breakthrough in understanding amylin receptor mechanisms that could accelerate the development of next-generation obesity drugs. The study, published in Science Signaling, reveals new insights into how amylin receptors function and provides pharmaceutical companies with previously unavailable tools for drug development.
Novel Methods Enable Receptor-Specific Drug Analysis
The research team, led by Augen Pioszak, Ph.D., an associate professor of biochemistry and physiology at the University of Oklahoma College of Medicine, developed new biochemical and pharmacological methods that allow researchers to understand exactly what drugs in development do at each of the three amylin receptors.
"This paper shows the new biochemical and pharmacological methods we developed that will enable the field, for the first time, to understand exactly what drugs in development do at each of the three amylin receptors," Pioszak said. "Amylin receptors are very complicated, and each has very different and unique properties. What we have discovered has eluded researchers for many years, and we believe our findings will advance drug development."
Amylin's Role in Appetite and Blood Sugar Control
Amylin is a hormone secreted from the pancreas alongside insulin after eating, controlling appetite and blood sugar by activating three different receptors in the brain. These amylin receptors belong to the same family as GLP-1 receptors, which are targeted by established obesity drugs like semaglutide, marketed as Ozempic and Wegovy.
Sandra Gostynska, the doctoral student who serves as lead author and made the seminal findings, emphasized the pharmaceutical industry's growing interest in this area. "There has been a lot of interest in the pharmaceutical industry for developing new obesity drugs," Gostynska said. "What we have done is given the field new tools for understanding how a drug can affect amylin receptors."
Key Discoveries About Receptor Structure and Function
The research yielded two major findings that could reshape amylin-based drug development:
Receptor Subunit Architecture
The three amylin receptors share a core component but have differing accessory subunits. Pioszak's team used an analogy to explain this complexity: the receptors wear common attire but dress it up with different accessories to make each distinct. Understanding how to target this distinctiveness may be crucial for creating drugs that optimally control appetite and achieve maximum weight loss with minimal side effects. Gostynska developed a specific laboratory procedure to analyze this receptor architecture.
Drug-Induced Subunit Interactions
The researchers discovered that drugs have the potential to either pull the receptor subunits together or push them apart. This mechanism could be important for drug development because drugs may act differently depending on whether they push or pull the subunits.
Implications for Current Drug Development
Pharmaceutical companies are already developing drugs based on amylin, and Pioszak's research provides crucial clarity for understanding what occurs when drugs target these complex receptor systems.
"We believe our findings will further the study of drugs because what pharmaceutical and biotech companies want to know is what their drug does at each amylin receptor," Pioszak said. "Now we have a method of answering those questions that were previously unanswerable."
The breakthrough comes at a time when the pharmaceutical industry is intensively pursuing new obesity treatments, building on the success of GLP-1 receptor agonists. The ability to precisely understand how amylin-based drugs interact with each receptor type could enable the development of more targeted and effective obesity therapies with improved side effect profiles.
