An Overview, Advantages and Therapeutic Potential of Nonpeptide Positive Allosteric Modulators of Glucagon‐Like Peptide‐1 Receptor

Due to uncomfortable injection regimens of peptidic agonists of glucagon‐like peptide‐1 receptor (GLP‐1R), orally available nonpeptide positive allosteric modulators (PAMs) of GLP‐1Rs are foreseen as the possible future mainstream therapy for type 2 diabetes. Herein, current GLP‐1R PAMs are reviewed. Based on the effectiveness and in silico predicted physicochemical properties, pharmacokinetics, and toxicity, possible candidates for further development as oral drugs were selected. The suggestion is that GLP‐1R PAMs might be used orally alone or in combination with dipeptidyl peptidase‐4 (DPP‐4) inhibitors, which could offer an optimal treatment option next to metformin monotherapy in type 2 diabetes mellitus, or in a wider spectrum of indications. Quercetin acts as a GLP‐1R PAM and DPP‐4 inhibitor, and therefore, might be considered as a pioneering agent with a dual mechanism of action, in terms of GLP‐1R positive allosteric modulation and DPP‐4 inhibition for potentiating GLP‐1 dependent effects. Now by mouth: Glucagon‐like peptide‐1 (GLP‐1) receptor positive allosteric modulators (PAMs) are potential candidates as oral agents for treatment of type 2 diabetes mellitus, or in a wider spectrum of indications. One example, quercetin, may be considered as a pioneering dual agent, GLP‐1 receptor PAM and dipeptidyl peptidase‐4 inhibitor, for potentiating GLP‐1‐dependent effects.