Development of novel therapeutic agents designed to enhance insulin secretion through trace amine-associated receptor 1 (TAAR1) activation

Rhianna Lenham, PhD
Department of Biochemistry

Date: March 17, 2025
Time: 1:00 p.m. to 2:00 p.m. 
Room: CSF 1302

Abstract:

It is widely considered that insulin is the most important hormone involved in metabolic homeostasis. Affecting over 400 million people worldwide, diabetes mellitus is a metabolic disorder caused by defects in insulin action, secretion, or both. Although there are several oral hyperglycaemic agents which have been developed to manage type 2 diabetes, their effectiveness often declines over time.  Trace amine-associated receptor 1 (TAAR1) is a G protein-coupled receptor expressed throughout the body including pancreatic β-cells. Pancreatic TAAR1 can amplify insulin secretion via the activation of protein kinase A and Epac signalling cascades, thus it is recognised as a potential therapeutic target for novel oral hyperglycaemic drugs. A crystal structure of human TAAR1 is yet to be determined. Therefore, machine learning techniques were implemented for structure determination, leading to over 1000 potential models generated and ranked based on their ability to dock four known TAAR1 ligands resulting in an accurate and reliable computational representation of TAAR1. Furthermore, three structure-activity relationship studies, composed of novel and literature compounds have been designed, synthesised and their activity profile within pancreatic INS-1 cells established. Within the diabetic phenotype, compounds were reported to enhance insulin secretion, with further screening completed to indicate this effect was through interactions with TAAR1. As part of this communication, I will discuss the results of my PhD project, via describing the synthetic routes and pharmacological response of all structure-activity relationship studies as well as the results obtained from the molecular docking and how this leads to my current research at MUN.