A recent study suggests that by activating certain bitter taste receptors, it is possible to open up lung passageways, making them a promising target for the treatment of asthma and chronic obstructive pulmonary disease (COPD).

It may come as a surprise, but bitter taste receptors are not solely present in the mouth. In fact, these receptors have been found in various parts of the body, such as the airways.

By stimulating these receptors, it is possible to open up the air passages in the lungs, making them a promising target for addressing respiratory conditions like asthma or chronic obstructive pulmonary disease (COPD).

A recent study published in ACS’ Journal of Medicinal Chemistry reveals that scientists have developed a powerful and specific compound that could pave the way for therapies targeting bitter taste receptors.

Of the 25 diverse types of bitter taste receptors, the TAS2R14 subtype is one of the most broadly dispersed across tissues beyond the oral cavity. Despite its prevalence, researchers are still uncertain about the receptor’s structure and have not identified the particular ligand or compound responsible for activating it within the body.

While only a few synthetic compounds, including the nonsteroidal anti-inflammatory drug (NSAID) flufenamic acid, have been found to bind and activate TAS2R14s, these compounds lack potency and share no significant structural characteristics.

As a result, developing a more effective ligand has been challenging. Despite this, a team led by Masha Niv, Peter Gmeiner, and their colleagues have used flufenamic acid as a foundation to create and produce analogs with enhanced properties.

Subsequently, the team aimed to expand their research by designing a series of more effective TAS2R14 ligands.

Building upon their previous research that had identified certain structural features that enhance potency, the researchers created numerous new variations. These compounds were then tested in a cell-based assay that gauges receptor activation.

Through this approach, the team discovered that substituting a phenyl ring with a 2-aminopyrimidine and replacing a carboxylic acid group with a tetrazole yielded a highly promising strategy.

Among the new ligands, one proved to be six times more potent than flufenamic acid, indicating that a lower quantity of the compound could generate an equivalent response as the NSAID.

Additionally, this particular ligand was notably selective for TAS2R14 compared to non-bitter taste receptors, a quality that could minimize potential side effects.

According to the researchers, these new compounds will be instrumental in elucidating the structure, mechanism, and physiological function of bitter taste receptors, as well as guiding the development of potential drug candidates aimed at targeting these receptors.

Source: 10.1021/acs.jmedchem.2c01997

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