Researchers Move Closer to Identifying New Class of Asthma, COPD Drugs Says New Study
Researchers in Baltimore have identified new compounds whichrelax airway muscles and may provide relief from shortness of breath for patients with COPD and asthma. The bitter-tasting compounds are at least as, if not more, effective than currently available agents used to manage these diseases, and may present new options for treatment.
The study was presented at the ATS 2011 International Conference in Denver.
“We have identified compounds that are more potent than our previously identified set of compounds, paving the way for development of bronchodilators for treating asthma and COPD,”
said study author Kathryn Robinett, MD, pulmonary and critical care fellow at the University of Maryland School of Medicine. “These compounds represent a new class of bronchodilator that
work through an entirely different mechanism than beta-agonists like albuterol, salmeterol and formoterol.” Bitter taste receptors on taste buds of the tongue are thought to have evolved to warn people that they may be ingesting a toxic substance, Dr. Robinett explained. Previous studies revealed these receptors are also present on the smooth muscle surrounding the airways, which constricts in patients with asthma and COPD, reducing the size of the airway and making breathing difficult.
“We had been looking for airway smooth muscle receptors that, when activated, can relax this muscle for the past five years, and we were excited to find compounds that caused profound relaxation, in both mouse and human airways,” she said.
For their study, the researchers examined compounds known to be bitter suggesting they may be effective in relaxing these airway muscles. Once potential compounds were identified, the
researchers administered these compounds to mouse airways to examine their effects. They found that bitter compounds were at least as effective as beta-agonists in relaxing smooth airway muscle. Relaxation of active tension in these muscles in mice approached 100 percent for most compounds, compared to 30 percent for the beta-agonist isoproterenol. In a more limited number of studies in human airways, they continue to find bitter compounds to be somewhat more effective than beta-agonists. More importantly, they appear to work in different ways
inside the cell, so the two classes of drugs can work together to treat moderate to severe obstructive lung disease.
“These findings continue to support data that bitter taste receptor agonists could be the next major class of therapeutics in treating asthma and chronic obstructive pulmonary disease,” Dr.
Robinett said.
Obstructive lung disease, including asthma and COPD, continues to be a significant source of morbidity and mortality affecting 300 million people worldwide. “Unfortunately, despite widespread use of inhaled corticosteroids and long acting beta-agonists, and environmental controls, as many as one-half of people in the U.S. alone have inadequate control of asthma,” Dr. Robinett said. “Bitter taste receptor agonists may add to our armamentarium of treatment options.” Despite their impressive efficacy, the researchers found many of the compounds activate only one or two of the six main bitter taste receptors on airway smooth muscle, meaning that they may not taste very bitter on the tongue, which has 25 bitter receptors. “We continue to be amazed at the breadth of substances that activate these receptors,” Dr. Robinett said. “The plant world is packed with agents that can be effective therapeutics at these targets, or can provide us with the ‘molecular backbone’ to synthesize compounds that would be
better drugs.”
Dr. Robinett said this study is just the first step in a much larger task: identifying the compounds
which offer optimal results for COPD and asthmatic patients.
“There are over 10,000 compounds that are known to be bitter taste receptor agonists,” she said.
“These come from plants, including medicinal herbs and food additives, or are synthetic agents
that are used for entirely different medical reasons (such as chloroquine for treating malaria). So,
we have not only uncovered a previously unrecognized way to open the airways in asthma and
COPD, but we have many compounds to consider either ‘as they are,’ or as backbones for
synthesizing a new agent.
“Our challenge, then,” Dr. Robinett continued, “is to find safe agents that are not so bitter-tasting
as to make them unpalatable, and yet are able to affect the degree of relaxation of airway
smooth-muscle that we have found in experimental models.
“Our immediate focus is to gain a better understanding of second messenger pathways and
desensitization of bitter taste receptors, to continue to search for more agonists, and to carry out
toxicology studies on selected compounds,” Dr. Robinett said. “Then, with a set of our ‘best
compounds’ we will begin the process for Phase 1 clinical trials.”
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“Bitter Taste Receptor Signaling On Airway Smooth Muscle: A Highly Efficacious Pathway For
Treating Obstructive Airway Disease” (Session A30, Sunday, May 15, 8:15-10:45 a.m., Room
501-502 (Street Level), Colorado Convention Center; Abstract 16969)
* Please note that numbers in this release may differ slightly from those in the abstract. Many of
these investigations are ongoing; the release represents the most up-to-date data available at
press time.
Abstract 16969
Bitter Taste Receptor Signaling On Airway Smooth Muscle: A Highly Efficacious Pathway For Treating
Obstructive Airway Disease
Type: Scientific Abstract
Category: 08.07 – LAM: Fundamental Mechanisms (RSF)
Authors: K.S. Robinett, D.A. Deshpande, S.B. Liggett; University of Maryland School of Medicine – Baltimore,
MD/US
Abstract Body
Rationale: We have recently shown expression of bitter taste receptors (TAS2R) on human airway smooth
muscle (HASM), that when activated by bitter agonists such as quinine and saccharin, evoke profound airway
relaxation. The relaxation is due to an increase in intracellular calcium ([Ca2+]i) that is temporally and spatially
restricted in HASM to a pool that activates the large conductance calcium-dependent potassium channel
(BKCa). However, the apparent affinity (potency) for these classic bitter tastants for HASM TAS2Rs is low, which
may limit therapeutic utility. Here we carried out biochemical and physiological studies to identify high-affinity
agonists acting at HASM TAS2Rs.
Methods: We utilized high throughput fluorescence-based screening (HTFS) of Fluo-4 AM loaded HASM cells
using libraries of compounds with structures suggesting that they may be agonists at one or more of the
TAS2Rs expressed on HASM (TAS2R10, 14, 31, 5, 4 and 19). Dose-response studies were used to determine
potency and efficacy. In confirmatory studies of the more potent compounds, HASM inositol phosphate (IP)
accumulation (an upstream event of [Ca2+]i) and intact airway relaxation studies (the final physiological
response) in isolated mouse tracheas, were also carried out.
Results: At high concentrations (1 mM) multiple previously unknown bitter-like compounds stimulated HASM
[Ca2+]i 1.5- to 3-fold over baseline, indicating activity at one or more of the six TAS2R subtypes. Similarly, up to
3-fold increase in agonist-promoted IP accumulation was found, consistent with the proposed TAS2Rgustducin-
ß?-PLCß-IP3 pathway in HASM. Dose-response studies with the HTFS-positive hits revealed
EC50values for some compounds in the nanomolar to low micromolar concentrations for the [Ca2+]i response. In
isolated airways of mice, the most potent of these were studied to ascertain potency and efficacy values for
relaxing acetylcholine constricted airways. There was a high correlation between these values for assessing
TAS2Rs in the cell-based [Ca2+]i assays vs. the relevant physiologic response. Relaxation of active tension
approached 100% for most compounds (as compared to 30% for the ß-agonist isoproterenol). This degree of
efficacy was found regardless of the TAS2R agonist being a “high”- or “low” affinity compound.
Conclusions: HTFS and IP accumulation studies in HASM, and, physiological studies in intact airways, have
revealed clinically favorable potency and efficacy profiles of novel TAS2R agonists. These compounds may be
useful therapeutics in aerosolized form in the treatment of asthma and COPD. Structural modification of these
compounds may further enhance their affinity for TAS2Rs.