There are bitter taste receptors not only in the human mouth, but also in the lungs. Researchers have harnessed the natural ability of these receptors to dilate airways to create powerful new drugs that could change the way diseases like asthma and COPD are treated.
The bitter receptor subtype TAS2R14 is found on smooth muscle of the tongue and airways, and activation of TAS2R14 causes bronchodilation or smooth muscle relaxation, widening the airways. The action of TAS2R14 is more potent than existing beta-adrenergic receptor agonist bronchodilators, which are currently the mainstay treatment for conditions such as asthma and chronic obstructive pulmonary disease (COPD).
Broadly speaking, asthma and COPD are caused by a narrowing of the airways called bronchoconstriction. Airway smooth muscle in people with asthma contracts, causing inflammation and excessive mucus production, making breathing difficult. In COPD patients, an umbrella term that includes emphysema and chronic bronchitis, airway narrowing is caused by irreversible lung damage. Both conditions cause shortness of breath, wheezing and coughing and require treatment with bronchodilators or inhaled or oral steroids.
Scientists have known about the TAS2R14 receptor in the human lung for some time, but its structure has remained a mystery. The existence of natural he-TAS2R14 ligands (chemicals such as drugs that bind to the receptor) that activate the receptor also remains elusive.
Many synthetic compounds, such as the non-steroidal anti-inflammatory drug (NSAID) flufenamic acid, are known to bind and activate the TAS2R14 receptor, but are less potent. Researchers then set out to design more potent compounds that take advantage of the bronchodilatory effects of TAS2R14.
Using flufenamic acid as a starting point, we combined computational design and chemical synthesis to create better-characterized analogues (drugs with physical structures similar to flufenamic acid).
Having discovered compounds with enhanced potency, they chemically altered these analogues and tested them in cell-based assays to find the ones that caused maximal TAS2R14 receptor activation.
One of the new compounds, which the researchers named 28.1, turned out to be six times more potent than flufenamic acid. The compound was also highly selective for the TAS2R14 receptor compared to non-bitter receptors, potentially minimizing side effects of the drug.
The discovery of 28.1 has given scientists a better understanding of how bitter taste receptors in the airways work. It also increases the likelihood that drugs that target these receptors will be developed, leading to more effective drug treatments for asthma and her COPD patients.
“Our newly described TAS2R14 agonists serve as valuable tools to better understand the mechanisms and physiological functions of bitter taste receptors, and may lead to the development of drug candidates targeting this intriguing family of membrane proteins.” It will lead,” said the researchers.
This research Journal of Medicinal Chemistry.
Source: American Chemical Society
