Overton’s rule says that the easier it is for a chemical to dissolve in a lipid (fat) the easier and faster it will be transported into a cell. The Rule was first outlined in the 1890s by Ernst Overton of the University of Zürich. He declared that substances that dissolve in lipids pass more easily into a cell than those that dissolve in water.
He then set forth an equation that predicted how fast that diffusion would happen. One of the key parameters in that equation is K which defines the lipophilicity (oil-liking nature) of the chemical. The higher the value of K, the faster the predicted cell permeation rate. For over a century, medicinal chemists have used this relationship to shape their studies and clinical trials.
A team of electrochemists from the University of Warwick used a combination of a confocal microscope and an ultramicroelectrode to study what really happens when a chemical crosses a cell membrane. Advances in technology enabled them to position an ultramicroelectrode incrediblely close to the membrane boundary (roughly 20 microns away; ca. 1/3rd the thickness of a human hair) where it was used to generate a range of acids that should be able to diffuse relatively easily into a cell. These techniques allowed every step of the diffusion process to be directly examined. Previous studies had not been able to observe every step of the process and often required artificial stirring of the solutions.
The results stunned the researchers. While the acids did diffuse across a lipid membrane, they did so at rates that were diametrically opposite to the predictions of the Rule, i.e. the most lipophilic molecules were actually transported slowest. The researchers studied four acids (acetic, butanoic, valeric, and hexanoic) that had increasingly larger “acyl” (or carbon) chains. The longer the carbon chain, the easier the chemical dissolves in lipids and, therefore, according to Overton, the faster they should diffuse across a lipid membrane. In fact, the University of Warwick researchers observed that for these four acids the exact opposite is true: the easier it is for an acid to dissolve in a lipid, the slower it is transported across the membrane.
The research team will now use their technique to examine the diffusion into cells of a range of other chemicals. The lead researcher on the study from the University of Warwick, Professor Patrick Unwin, said:
“This was a surprising and exciting finding. Our direct observations appear to totally undermine a key rule that has withstood the test of time for over a century. We will now make observations with a range of other chemicals, and with other techniques, to further elucidate the molecular basis for our observations. Text books will have to be rewritten to revise a rule that has been relied on for over a century. Advanced techniques, such as the one we have developed, should give much clearer insight into the action of a wide range of drug molecules, which will be of significant interest to drug developers.”
Peter Dunn | alfa
A novel synthetic antibody enables conditional “protein knockdown” in vertebrates
20.08.2018 | Technische Universität Dresden
Climate Impact Research in Hannover: Small Plants against Large Waves
17.08.2018 | Leibniz Universität Hannover
There are currently great hopes for solid-state batteries. They contain no liquid parts that could leak or catch fire. For this reason, they do not require cooling and are considered to be much safer, more reliable, and longer lasting than traditional lithium-ion batteries. Jülich scientists have now introduced a new concept that allows currents up to ten times greater during charging and discharging than previously described in the literature. The improvement was achieved by a “clever” choice of materials with a focus on consistently good compatibility. All components were made from phosphate compounds, which are well matched both chemically and mechanically.
The low current is considered one of the biggest hurdles in the development of solid-state batteries. It is the reason why the batteries take a relatively long...
New design tool automatically creates nanostructure 3D-print templates for user-given colors
Scientists present work at prestigious SIGGRAPH conference
Most of the objects we see are colored by pigments, but using pigments has disadvantages: such colors can fade, industrial pigments are often toxic, and...
Scientists at the University of California, Los Angeles present new research on a curious cosmic phenomenon known as "whistlers" -- very low frequency packets...
Scientists develop first tool to use machine learning methods to compute flow around interactively designable 3D objects. Tool will be presented at this year’s prestigious SIGGRAPH conference.
When engineers or designers want to test the aerodynamic properties of the newly designed shape of a car, airplane, or other object, they would normally model...
Researchers from TU Graz and their industry partners have unveiled a world first: the prototype of a robot-controlled, high-speed combined charging system (CCS) for electric vehicles that enables series charging of cars in various parking positions.
Global demand for electric vehicles is forecast to rise sharply: by 2025, the number of new vehicle registrations is expected to reach 25 million per year....
17.08.2018 | Event News
08.08.2018 | Event News
27.07.2018 | Event News
20.08.2018 | Information Technology
20.08.2018 | Life Sciences
20.08.2018 | Information Technology