New study overturns century-old rule of chemistry

Washington, August 26 : A new study, by research chemists at the University of Warwick in the UK, has challenged a century old rule of chemistry that defined how quickly key chemicals can pass across cell walls, thus having major implications for the development and testing of many future drugs.

The new observations of the Warwick researchers suggest that the real transport rates could be up to a hundred times slower than predicted by the century old "Overton's Rule.

According to Overton's rule, 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 Zurich.

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.

Now, 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), where it was used to generate a range of acids that should be able to diffuse relatively easily into a cell.

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.

According to Professor Patrick Unwin, the lead researcher on the study, "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."

ANI