Structure-Activity Relationship Study of T1R2/T1R3 Positive Allosteric Modulators and Evaluation of Their Enhancing Effect on Various Sweeteners

The sweet taste receptor T1R2/T1R3 belongs to the family of G protein coupled receptors and recognizes various sweet substances from small compounds to proteins. We have previously reported unnatural tripeptides that function as positive allosteric modulators (PAMs) of the T1R2/T1R3. The structures were classified into three parts-head, linker, and tail-as compared with known T1R2/T1R3 PAMs. Here, we conducted a structure-activity relationship study of the tail structure to further understand the structural features of the T1R2/T1R3 PAMs. Moreover, we evaluated the enhancing effect of these PAMs on various sweeteners. In conclusion, we found that both hydrophilic alpha-amino acids and the hydrophobicity of the alpha-amino acid side chain are important for enhancing activity for this receptor. These PAMs also showed the receptor enhancing activity against sugar-like T1R2/T1R3 agonists such as sucrose, sucralose, and fructose.