Bitter Taste Receptors May Save You from Asthma and COPD

Asthma and chronic obstructive pulmonary disease (COPD) treatment mainly relies on the use of bronchodilators and corticosteroid drugs. More recently, monoclonal antibody therapies (biologics) targeting specific cytokines and their functions have been used. Although these approaches provide relief, questions remain on their long-term efficacy and safety. Now, researchers have reported in ACS’ Journal of Medicinal Chemistry about a newly designed potent and selective compound that could lead the way to effective therapies for asthma and COPD. They are bitter taste receptors.

Bitter Taste Receptors for Asthma Therapeutics

Surprisingly, bitter taste receptors are not only located in the mouth but also elsewhere in the body, including the airways. Activating those receptors opens lung passageways, so they’re a potential target for treating asthma or chronic obstructive pulmonary disease (COPD).

Among the 25 different types of bitter taste receptors, the TAS2R14 subtype is one of the most widely distributed in tissues outside the mouth. Scientists are uncertain about the structure of the receptor, and they have not identified the particular compound or “ligand” in the body that activates it.

However, a few synthetic compounds, such as 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, researchers used flufenamic acid as a starting point to design and synthesize analogs with improved properties. Next, they 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.

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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 the development of drug candidates to target them.

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Source-Eurekalert