Non‐peptide agonists and positive allosteric modulators of glucagon‐like peptide‐1 receptors: Alternative approaches for treatment of Type 2 diabetes

摘要

Glucagon‐like peptide‐1 (GLP‐1) receptors belong to the pharmaceutically important Class B family of GPCRs and are involved in many biologically significant signalling pathways. Its incretin peptide ligand GLP‐1 analogues are effective treatments for Type 2 diabetes. Although developing non‐peptide low MW drugs targeting GLP‐1 receptors remains elusive, considerable progress has been made in discovering non‐peptide agonists and positive allosteric modulators (PAMs) of GLP‐1 receptors with demonstrated efficacy. Many of these compounds induce biased signalling in GLP‐1 receptor‐mediated functional pathways. High‐quality structures of GLP‐1 receptors in both inactive and active states have been reported, revealing detailed molecular interactions between GLP‐1 receptors and non‐peptide agonists or PAMs. These progresses raise the exciting possibility of developing non‐peptide drugs of GLP‐1 receptors as alternative treatments for Type 2 diabetes. The insight into the interactions between the receptor and the non‐peptide ligand is also useful for developing non‐peptide ligands targeting other Class B GPCRs.