Spinneret - Weaving the chemical web one molecule at a time...

A century-old rule used throughout the pharma industry may have been overturned by new research in the UK. Researchers at the University of Warwick have demonstrated that drug transport rates across cell membranes may be hundreds of times slower than are predicted by Overton’s Rule, which could have serious implications for developing and testing new drugs.

Put simply, Overton’s Rule says that the more lipophilic a compound is, the faster it will enter a cell. The Rule was first outlined in the 1890s by Ernst Overton of the University of Zürich. He quantified the rule to allow biochemists and others to predict how fast the membrane crossing would take place. One of the key parameters in his equation is K, lipophilicity. Bigger K, faster transport.

For over a century, medicinal chemists have used this relationship to shape their studies and clinical trials.

Now, a confocal microscopy study used in conjunction with an ultramicroelectrode led by Patrick Unwin has allowed the team to follow every step of the membrane-crossing process. The results are stunning. While the test compounds (acids) did diffuse across a lipid membrane, they did so at rates that were diametrically opposed to those prediction by Overton’s Rule. 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.

The Warwick work showed instead that the most lipophilic molecules were actually transported the slowest.

REFERENCE: Proc Natl Acad Sci: Quantitative visualization of passive transport across bilayer lipid membranes

Molecules | No Comments »

Some people would pay anything for a quickfix pill for their sex lives or to slow the inevitable aging process. Now, US scientists have found a new class of small molecule in the molecular biologist’s favorite nematode worm, Caenorhabditis elegans, a blend of which apparently not only attract mates but also slow the development of larvae for months.

The soil-dwelling nematode is used as a model organism for lots of human diseases and in aging research because despite the apparent differences between ourselves and the nematode, we share much of our underlying biology with the worm.

Writing in Nature, Frank Schroeder, of Cornell University, Jagan Srinivasan, of California Institute of Technology, and colleagues describe the new compounds, ascarosides, and reveal data that show how they extend lifespan in C. elegans as well as acting as sex pheromones for the wriggly critter. The work essentially ties together at the molecular level two superficially disparate life processes - sex and death.

So, are we likely to see a human version of the ascarosides for attracting a sex partner and warding off old age. Short answer is no. Although we share some of the molecular biology of this nematode, there are a few too many differences to make such a pill even remotely possible…at any price.

Srinivasan, J., Kaplan, F., Ajredini, R., Zachariah, C., Alborn, H.T., Teal, P.E., Malik, R.U., Edison, A.S., Sternberg, P.W., Schroeder, F.C. (2008). A blend of small molecules regulates both mating and development in Caenorhabditis elegans. Nature DOI: 10.1038/nature07168

Molecules | No Comments »