Month: July 2024

Doxepin is an antihistaminic, antidepressant, and sleeping aid that has two geometric isomers—molecules with equal chemical formulas but different 3D arrangements. While its Z-isomer is known to be more effective than its E-isomer, the precise nature of its binding to the histamine H1 receptor remained elusive. Now, in a recent study, researchers from Japan thoroughly addressed this knowledge gap through an innovative experimental protocol, paving the way to next-generation antihistamines with fewer side effects.

Even if two molecules have the exact same chemical formula and the same number and types of bonds, their three-dimensional arrangements can still be different. While some people might mistakenly disregard this as a minor detail, even simple changes in the position or orientation of a functional group can dramatically affect the biological properties of a molecule, sometimes rendering an otherwise benign substance into a highly toxic one. Thus, the study of such possible molecular variants, called ‘geometric isomers,’ is essential in the field of drug development.

Doxepin stands out as a notable example of a drug that is commercialized as a mixture of two geometric isomers, namely the E- and Z-isomers. Both doxepin isomers bind to histamine H1 receptor (H1R), which is expressed throughout the central nervous system, smooth muscle cells, and vascular endothelial cells. Besides its use as an antihistaminic drug, doxepin is also typically used as an antidepressant and sleeping aid. While biological tests in animals have shown that the Z-isomer is more effective than the E-isomer, the differences in affinity to H1R between the E- and Z-isomers are unknown. Moreover, the specifics of how these compounds actually bind to H1R remain elusive.

Against this backdrop, a research team from Tokyo University of Science, Japan, set out to clarify the finer details of the interactions between doxepin isomers and H1R. Their latest paper, which was published on June 25, 2024, in the Journal of Molecular Recognition, was co-authored by Professor Mitsunori Shiroishi, Mr. Hiroto Kaneko, and Associate Professor Tadashi Ando, among others. This study is a follow-up to past work done by Prof. Shiroishi and colleagues. “We previously revealed the crystal structure of the complex formed by H1R and doxepin, but we were unable to determine which isomer was bound,” he explains, “We then came up with a method to determine the binding affinity of the isomers, and thus carried out this study.”

To achieve this challenging goal, the researchers first produced a customized yeast expression vector by strategically inserting the H1R gene into it. This vector was used to modify yeast cultures so that they produce H1R. After retrieving the membranes from these cells, they applied a solution containing commercial doxepin, producing H1R-doxepin complexes. Following extraction and purification of these complexes, they removed any excess (unbound) doxepin. Finally, by denaturing the H1R receptors, they could free the bound doxepin molecules and measure their numbers in a high-performance liquid chromatography setup.

Using this protocol, the researchers could accurately quantify the amount of each isomer that was bound to the extracted receptors, which is directly tied to their relative binding affinity. They found that the affinity to H1R of the Z-isomer was over five times higher than that of the E-isomer.

The team then delved deeper into the nature of how doxepin isomers bind to H1R. Through experiments on a mutant variant of H1R coupled with molecular dynamics simulations, they revealed that the Thr112 side chain in the ligand-binding pocket of H1R creates a chemical environment that enhances selectivity for the Z-isomer.

Taken together, the findings of this study shed light on how a widely used small molecule drug interacts with an important cellular receptor. “Our efforts could serve as the basis for designing next-generation antihistamines that are more effective and have fewer side effects,” highlights Prof. Shiroishi, “Worth noting, this newfound knowledge will be useful for designing compounds that bind not only to H1R, but also other disease-relevant target proteins.”

The rational design of future drugs, aided and validated by computational techniques like molecular dynamics simulations, could usher in a new era in medicine. More specifically, by understanding the binding properties of isomers in detail, many small-molecule drugs could be made more effective, safer, and better suited for targeted therapies.

Let us hope this vision of the future becomes a reality soon!

Solid oxide fuel cells (SOFCs) are a promising avenue to meet global demands for clean energy. They can produce electricity through environmentally friendly electrochemical reactions. However, existing SOFCs operate at high temperatures, which lowers their efficiency. Now, researchers from Japan have developed a novel perovskite-based anode material for SOFCs that exhibits mixed hole–proton conduction at medium-range temperatures. Their findings will help establish more efficient energy technologies, leading the way to more sustainable societies.

Amidst the ongoing energy and climate crises, the stakes have never been higher. We are pressed for time to find better ways of producing clean energy to replace fossil fuels. Thus far, fuel cells appear to be one of the most promising research directions. These electrochemical devices can produce electricity directly from chemical reactions, which can be tailored to be environmentally friendly in terms of their reactants and outputs.

Various types of fuel cells exist, but solid oxide fuel cells (SOFCs) have attracted special attention from researchers. By operating without the need for a liquid electrolyte, they offer higher safety and are often easier to manufacture. Unfortunately, one of their main drawbacks is their high operating temperature. Conventional SOFCs need to be at over 700 °C to work properly, which limits their applicability, reduces their efficiency and power output, and often compromises their durability. Thus, proton-conducting SOFCs (PC-SOFCs), which can operate within a lower temperature range, are being investigated as a promising alternative.

Against this backdrop, a research team including Professor Tohru Higuchi from Tokyo University of Science has achieved a breakthrough in PC-SOFCs by developing a novel hole–proton mixed-conductor material. Their findings, which have been published in the Journal of the Physical Society of Japan on June 18, 2024, could pave the way for important technological advancements in energy technologies.

The material in question is a perovskite-type oxide ceramic with the formula BaCe0.4Pr0.4Y0.2O3−δ (BCPY). These particular dopants, namely Pr and Y ions, were selected based on previous works by members of the research team. They observed that BaCe0.9Y0.1O3−δ and BaPrO3−δ exhibited proton and hole (a type of positive charge carrier) conduction, respectively. Thus, they theorized that co-doping with both Pr and Y might lead to high proton–hole mixed conductivity.

Such a material could be used in the anode electrode of PC-SOFCs, as Prof. Higuchi explains: “The Pt metal electrode used in other fuel cells has issues, such as a large drop in power output because electrochemical reactions occur only at the three-phase interface where the fuel gas/electrode/electrolyte intersect. To solve this issue, a dense membrane with mixed conduction could be useful for improving the performance of PC-SOFC by expanding the electrochemical reaction area.”

Using a sputtering technique, the researchers produced thin films of BCPY and carefully analyzed its conduction properties, seeking to find evidence of mixed proton–hole conduction. To this end, they established a quantitative evaluation method to determine oxygen vacancies using X-ray absorption spectroscopy and defect chemistry analysis. Through these and several additional experiments, including synchrotron radiation photoelectron spectroscopy for electronic band structure analysis, they found substantial evidence that mixed hole–proton conductivity can occur on the surface of the proposed electrode material.

Notably, BCPY electrodes exhibited a high conductivity of over 10−2 S.K/cm at 300 °C, which outlines a bright future not only for PC-SOFCs, but for other technologies as well. “If we can further confirm that BCPY thin films do enable hole–proton mixed conductivity, BCPY may become a novel oxide material for not only PC-SOFC anode electrode membranes but also electric-double-layer-transistors,” highlights Prof. Higuchi. To clarify, this transistor technology can address the scalability and miniaturization problems of conventional transistors, which will be crucial to developing artificial intelligence systems and increasing the computational capacity of personal electronic devices.

In any case, this study sheds some much-needed light on new electrode materials for PC-SOFCs. With further advances in this exciting field, electrochemical energy generation could eventually enable us to power up our homes and cars with cleaner electricity, paving the way to more sustainable societies.