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| Poster #308 Investigation of the Pharmacodynamic Properties of TAS1R2/TAS1R3(T1R2/R3) Ligands with Distinct Binding Sites Using Rapid Throughput Taste Discrimination with Human Subjects |
| Nicole McKeeby, Kaday Sesay, Kyle Palmer Opertech Bio, Inc., Philadelphia, PA, United States |
T1R2/R3 is a class C heterodimer GPCR, with multiple binding sites across both TAS1R2 and TAS1R3 protomers that accommodate many different ligands, of various pharmacological actions, from a broad array of chemical classes. With so many pharmacological tools available, human sweet taste behavior should be an ideal model to study principles of receptor pharmacodynamics in vivo. The TāStation® is a rapid throughput, operant taste discrimination technology with the capacity required for carrying out robust concentration-response analysis of human tastant receptor ligands. We are using TāStation® to pharmacologically characterize human taste response to agonists, antagonists, and positive- and negative-allosteric modulators (PAMs and NAMs) operating at different binding sites on T1R2/R3. Concentration-response analysis of the saccharide sweeteners sucrose, fructose, glucose, and sucralose, all of which bind to a site in the amino terminus “Venus flytrap domain” (VFD), yielded EC50s of 33, 118, 127, and 0.08 mM. FEMA 4774, a T1R2/R3 PAM in vitro, at 0.03 mM decreased sucrose EC50 and Hill coefficient values approximately 2.5-fold. However, 0.03 mM FEMA 4774 had no measurable impact on fructose and glucose concentration-response functions. Lactisole, a T1R2/R3 NAM with a binding site located in the transmembrane domain of the TAS1R3 protomer, eliminated taste responses to all but the highest concentrations of sucrose, fructose, and glucose. Cyclamate also binds to this site, but at 0.1 mM interacted synergistically with sucrose, and exhibited intrinsic agonist activity at 0.2 and 0.4 mM. Studies of lactisole, FEMA 4774, and cyclamate effects on T1R2/R3 agonists with binding sites elsewhere on the receptor are ongoing. |