TAS2R38

Taste receptors for bitter substances are not only found on the tongue but also on cells outside the oral cavity. As a new study now shows, extraoral bitter taste receptors could also serve as endogenous sensors for bile acids. This discovery suggests that, in addition to food components, endogenous substances may have influenced the evolution of bitter taste receptors. Furthermore, the study provides new approaches to explore the health effects of food constituents in which extraoral bitter taste receptors are involved. Taste receptors for bitter substances are not only found on the tongue but also on cells outside the oral cavity. As a new study by the Leibniz Institute for Food Systems Biology at the Technical University of Munich now shows, extraoral bitter taste receptors could also serve as endogenous sensors for bile acids. This discovery suggests that, in addition to food components, endogenous substances may have influenced the evolution of bitter taste receptors. Furthermore, the study provides new approaches to explore the health effects of food constituents in which extraoral bitter taste receptors are involved. As taste sensors, bitter taste receptors serve to detect and avoid potential toxins in food. Relatively recent findings also indicate that bitter taste receptors are also found on cells of the lung, brain, and gastrointestinal tract, and on blood and sperm cells. A fact that suggests further, less well-studied receptor functions in the body, especially since the human body also produces bitter substances itself. Based on these findings, the question arises whether bitter taste receptors evolved primarily as taste receptors or rather as endogenous sensors interacting with endogenous bitter substances. The latter, of course, would require that concentrations of endogenous substances in the corresponding body fluids be sufficient to activate endogenous bitter taste receptors on extraoral tissues and cells. Bile acids are endogenous bitter substances Bile acids are a good example of endogenous bitter substances and are present in various body fluids. Therefore, a team led by Maik Behrens from the Leibniz Institute in Freising, Germany, investigated which of the approximately 25 human bitter taste receptor types respond to physiologically relevant bile acid concentrations. For this purpose, the team used an established cellular test system and combined functional experiments with molecular modeling approaches. The eight bile acids tested included primary, secondary, tertiary, and conjugated bile acids. As the team shows, five bitter taste receptor types respond to the bile acids tested. "In this context, the measured activation thresholds of the receptors matched very well the bile acid concentrations reported for human body fluids in the literature," says Florian Ziegler, a doctoral student at the Leibniz Institute who contributed significantly to the study. "Moreover, we were not only able to characterize the binding of bile acids to the bitter taste receptor TAS2R1 by modeling studies but even reproduced the differences of experimental activity data," adds Antonella Di Pizio, who heads the Molecular Modeling group at the Leibniz Institute. Bile acids activate extraoral bitter taste receptors "Our results suggest that there is indeed a physiological relationship between bile acids and certain extraoral bitter taste receptors and that the latter act as endogenous sensors of bile acid levels. They also support the hypothesis that not only external factors such as bitter food constituents have influenced the evolution of bitter taste receptors, but also endogenous ones," summarizes principal investigator Maik Behrens. However, further studies are urgently needed to clarify the exact biological functions of the extraoral receptors, the biologist continues. He adds: "Gaining a deeper understanding of these functions could provide valuable insights into the potential health effects of food components when they interact with the extraoral bitter taste receptor ligand systems."

Surprisingly, bitter taste receptors are not only located in the mouth, but also elsewhere in the body, including the airways. Activating those receptors opens up lung passageways, so they're a potential target for treating asthma or chronic obstructive pulmonary disease (COPD). Now, researchers report that they have designed a potent and selective compound that could lead the way to such therapies. Surprisingly, bitter taste receptors are not only located in the mouth, but also elsewhere in the body, including the airways. Activating those receptors opens up lung passageways, so they're a potential target for treating asthma or chronic obstructive pulmonary disease (COPD). Now, researchers report in ACS' Journal of Medicinal Chemistry that they have designed a potent and selective compound that could lead the way to such 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 are uncertain about the structure of the receptor, and they 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 of the compound was needed to produce a similar response as 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 development of drug candidates to target them, the researchers say.

California’s Soleno Therapeutics, a clinical-stage biopharmaceutical company, announced promising results of its diazoxide choline extended-release (DCCR) tablets in patients with Prader-Willi syndrome (PWS). Revealed during an oral presentation at the 2022 Endocrine Society Annual Meeting & Expo (ENDO), the data showed that one year of DCCR treatment led to significant improvements in patients’ lean body mass (p<0.0001) and the ratio of lean body mass to fat mass (p=0.0005). These positive changes were accompanied by a significant drop in fasting levels of insulin (p=0.0004) and leptin (p<0.0001). DCCR likewise induced significant improvements in insulin sensitivity (p=0.0033), partly due to the patients’ lower fat mass and better leptin resistance. Recipients also saw a significant increase in the cardioprotective marker adiponectin (p<0.0001). Of note, focusing the analysis on patients with obesity did not weaken DCCR beneficial effects. “These important results show that the benefits of DCCR also extend to positive changes in objective metabolic parameters, in addition to prior data demonstrating improvements in hyperphagia and behavioral symptoms of PWS,” Dr. Eric Felner of Emory University School of Medicine said in a statement. “These results further emphasize the potential for DCCR to be a meaningful treatment that improves multiple key symptoms of PWS, which has significant implications for patients and families struggling to manage this devastating disease.” The data presented at ENDO came from two trials: C601, a Phase III, randomized, double-blind, placebo-controlled study and C602, its ongoing open-label extension. A total of 82 PWS patients participated in the trials, of whom 40 had obesity. Patients were treated with DCCR tablets, which contain the crystalline salt of diazoxide and are administered once a day. Felner, who presented the latest results at ENDO, is a principal investigator of the C601/C602 trials. DCCR also demonstrated an acceptable safety pro a separate poster presentation at ENDO, delivered by Dr. Michael Woloschak, vice president of clinical development at Soleno. Common adverse events, such as peripheral edema, hyperglycemia and hypertrichosis, were consistent with previous experiences involving DCCR. PWS is a rare genetic disorder that affects around one in every 15,000 live births in the United States. Commonly, patients with PWS suffer from its hallmark symptom, hyperphagia, or being insatiably hungry. Hyperphagia causes patients to overeat, which, in turn, leads to uncontrollable weight gain. Often, PWS complications arise due to obesity. Currently, there is no approved treatment for the appetite and metabolic aspects of PWS, a great unmet need that Soleno hopes to fulfill. Perhaps due to the disease’s complex nature, Soleno is entering a relatively unoccupied PWS space with its DCCR tablets. In March, Tonix Pharmaceuticals’ investigational drug TNX-2900 was granted the orphan-drug designation by the United States Food and Drug Administration for the treatment of PWS. Unlike Soleno’s DCCR tablets, TNX-2900 comes in the form of a nasal spray to deliver a patent-protected formulation that can increase the specificity of the user’s oxytocin receptors. A month earlier, clinical-stage biopharma company Aardvark Therapeutics announced that after encouraging results from a Phase I first-in-human trial, it was initiating enrollment for a Phase II study to test its investigational drug ARD-101 in PWS. A first-in-class small-molecule drug, ARD-101 is designed to target the extraoral bitter taste receptors and was shown to be effective in promoting weight loss in preclinical studies. “With a majority of adults in the U.S. being either overweight or obese and no approved treatments for PWS, clearly there is a need to develop new effective treatments,” Dr. Tien Lee, M.D., chief executive officer of Aardvark, said in a statement. “ARD-101 represents such a candidate therapy that has demonstrated safety and tolerability in studies to date and offers the convenience of oral administration.”