Activation of bitter taste receptors, a potential target for treating COPD, asthma

Germany: Activating bitter taste receptors opens lung passageways, making them potential targets for treating chronic obstructive pulmonary disease (COPD) or asthma. A recent study published in the Journal of Medicinal Chemistry has reported the design of a potent and selective compound that could lead the way to such therapies.

Bitter taste receptors are located in the mouth and elsewhere in the body, including the airways.

Among the 25 different types of bitter taste receptors, the TAS2R14 subtype is among the most widely distributed in tissues outside the mouth. Scientists are uncertain about the receptor's structure and haven’t 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, 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 compound was needed to produce a response similar to 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 the development of drug candidates to target them, the researchers say.

Reference:

Lukas Waterloo, Harald Hübner, Fabrizio Fierro, Tara Pfeiffer, Regine Brox, Stefan Löber, Dorothee Weikert, Masha Y. Niv, and Peter Gmeiner Journal of Medicinal Chemistry 2023 66 (5), 3499-3521 DOI: 10.1021/acs.jmedchem.2c01997