Surprisingly, bitter taste receptors are not only found in the mouth, but also in other parts of the body, including the airways, and this can be good for clearing them out.
The nerve endings that detect bitter taste are found primarily in the mouth and have protected us throughout evolution, as many bitter substances in nature are poisonous. However, there are bitter taste receptors in other parts of the body, especially in the respiratory tract. Activation of these receptors dilates the pulmonary pathways, making them a potential target for the treatment of asthma or chronic obstructive pulmonary disease (COPD). Now, researchers report in the ACS Journal of Medicinal Chemistry that they have created a potent, selective compound that could pave the way for these therapies.
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 do not know the structure of the receptor and have not identified the specific compound or “ligand” in the body that activates it. However, some synthetic compounds, such as the nonsteroidal anti-inflammatory drug (NSAID) flufenamic acid, are known to bind to and activate TAS2R14.
But these synthetic compounds are not very potent and do not have similar structural characteristics, so they do not bind strongly to these receptors and their effect is limited. The researchers used flufenamic acid as a starting point to design and synthesize analogues with improved properties. The team then wanted to expand on this work to develop an even better set of TAS2R14 ligands.
Building on their previous findings that certain types of structures enhanced power, the researchers made several new variations. They tested these compounds in a cellular assay that measures receptor activation. This approach revealed that replacing a phenyl ring with a 2-aminopyrimidine and a carboxylic acid group with a tetrazole was a promising strategy. One of the new ligands was six times more potent than flufenamic acid, meaning that less compound was needed to produce a similar response to NSAIDs. This ligand was also highly selective for TAS2R14 compared to non-bitter taste receptors, which could minimize side effects. According to the researchers, the new compounds will help to elucidate the structure, mechanism and physiological function of bitter taste receptors and will guide the development of drugs targeting them.
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Discovery of 2-Aminopyrimidines as potent agonists for the TAS2R14 bitter taste receptor