Development of Transient Receptor Potential Melanostatin 5 Modulators for Sweetness Enhancement

The discovery of a family of G protein-coupled receptors (GPCRs) that can bind sweet, bitter, or umami tastants has established that these taste sensations are mediated by classical signal transduction cascades. Proteins downstream from the tastant binding GPCRs, such as the G,, protein gustducin, phospholipase C-beta 2 (PLC beta 2) and the Transient Receptor Potential Melanostatin 5 (TRPM5) ion channel, have been identified as critical components in the transduction of these taste sensations. Using modem pharmaceutical discovery technology, we have discovered prototype compounds that specifically enhance TRPM5 activity in the presence of low levels of surrogate tastants. Enhancers operating through this novel mechanism could potentially allow for full taste sensations to be experienced from reduced concentrations of nutritive sweeteners. (C) 2008 American Chemical Society