Interestingly, bitter taste receptors can be found outside of the mouth, such as in the airways, and other parts of the body. These receptors are a possible target for the treatment of asthma and chronic obstructive pulmonary disease because activating them widens the airways in the lungs (COPD). Currently, scientists announce in the Journal of Medicinal Chemistry of the American Chemical Society that they have created a potent and selective molecule that may pave the way for such treatments.
The TAS2R14 subtype is one of the 25 distinct types of bitter taste receptors and is most prevalent in tissues outside of the mouth. The exact composition or “ligand” in the body that triggers the receptor is unknown to scientists, who are also unsure of its shape. However, some artificial substances, including the nonsteroidal anti-inflammatory drug (NSAID) flufenamic acid, are known to bind to and activate TAS2R14s.
But these compounds aren’t very potent, and they don’t have similar structural features. These difficulties make it challenging to create a better ligand. Nevertheless, Masha Niv, Peter Gmeiner and colleagues used flufenamic acid as a starting point to design and synthesize analogs with improved properties. Next, the team wanted to extend that work to develop a set of even better TAS2R14 ligands.
Building on their earlier findings that certain types of structures enhanced potency, the researchers made several new variations. They tested these compounds in a cell-based assay that measures receptor activation. This approach revealed that replacing a phenyl ring with a 2-aminopyrimidine and substituting a tetrazole for a carboxylic acid group was a promising strategy. One of the new ligands was six times more potent than flufenamic acid, meaning less of the compound was needed to produce a similar response as the NSAID.
This ligand was also highly selective for TAS2R14 compared to non-bitter taste receptors, which could potentially minimize side effects. The new compounds will help shed light on the structure, mechanism and physiological function of bitter taste receptors and guide development of drug candidates to target them, the researchers say.
