The blood-brain barrier is a semi-permeable barrier that separates the extracellular fluid surrounding the brain from circulating blood. Separating the brain from the bloodstream, it protects the brain against any sort of toxins in the blood. Its protective nature is because of its high selectivity; however, this also means it is difficult to deliver therapeutics to the brain.​

It is still little understood on the molecular level how small molecules such as drugs cross the BBB via lipid diffusion. The McLain research group from the University of Oxford have been studying the interaction between small molecules and water at ISIS to gain insight into this problem. To understand how these small molecules cross the BBB, the group are studying the relevant molecules to see how they behave in a solution in order to gain more biologically relevant information.

The struggle to develop drugs which are able to cross the BBB has driven the development of both in vitro and computational models to better understand how drugs reach the central nervous system. In particular, the McLain group want to understand hydration as this information gives clues as to how drugs such as alprazolam, which is used to treat anxiety disorders, bind to receptors to take effect. Studying how and why certain drugs are able to cross the barrier could lead to identifying key properties needed in the development of new drugs.

Drugs that are able to successfully cross the BBB and work pharmacologically must strike a balance between hydrophilicity and hydrophobicity. The lipid barrier is mostly hydrophobic and so molecules that diffuse across the membranes of the BBB need to be highly lipid soluble. However, after passing through the barrier the molecule must be hydrophilic enough to move through the interstitial brain fluid to reach the brain. Therefore successful drugs must be able to balance these properties in order to perform their pharmacological function.

The McLain group have studied a variety of drugs at ISIS that are able to cross the BBB, including cocaine and alprazolam.

Cocaine is a stimulant that works by inhibiting the reuptake of certain neurotransmitters and it is able to cross the BBB easily. Using a combination of neutron diffraction on SANDALS​ and computational models, the researchers studied the structure of cocaine solution on the atomic scale. Cocaine is an amphiphilic drug, meaning it has both hydrophobic and hydrophilic regions of the molecule. The researchers found that cocaine’s conformation and hydration appear to help it cross this complex barrier.

The average conformation of cocaine may allow it to shield its hydrophilic regions whilst interacting with the hydrophobic environment of the barrier. Results suggest that cocaine is able to be both lipophilic and hydrophilic without having to undergo a protonation-deprotonation reaction, as previously speculated, in order to fully penetrate into the BBB.

In a parallel project, the Mclain group studied alprazolam, a member of the benzodiazepine family that includes some of the most prescribed medications across the world. The team examined the solvation of alprazolam to gain insight into its solubility and whether information on the hydration could be used to understand how this molecule might interact with receptor sites in the brain.  

The drug is believed to work, like all benzodiazepines, by binding to certain receptors in proteins and inducing anti-anxiety, sedative, and sleep-inducing properties, amongst others. As well as these targets, spectroscopies have suggested that alprazolam binds to a wider range of biological molecules including haemoglobin and DNA.

Although alprazolam is a commonly used drug and binds to many biological molecules, there is little structural information on its conformation and hydration in the bound and free states. The only crystal structure of alprazolam is an alprazolam-protein complex which shows many water interactions between the drug and the protein in the complex. Understanding how these waters relate to the solvation of small molecules has the potential to aid the understanding of the ability of drugs to cross the BBB.

At ISIS, the McLain group used neutron diffraction and molecular dynamics simulations to look at how water molecules interact with alprazolam. The researchers found that the preferred location of the water molecules aggregating around alprazolam corresponded to the bridging waters found in the crystal structure of the alprazolam-protein complex. This correlation has potential to increase our understanding of the ability of drugs to cross the blood-brain barrier and the team plan to continue their research into the relationship between small molecules and water using neutrons.

Ellie Welch

Johnston, A.J. et al.; Sridhar, A. et al.

Research date: July 2016

​The McLain Group, University of Oxford

Johnston, A.J. et al. On the atomic structure of cocaine in solution. Phys. Chem. Chem. Phys., 2016, 18, 991-999

DOI: 10.1039/C5CP06090G

Sridhar, A. et al. The solvation structure of alprazolam. Phys. Chem. Chem. Phys., 2016, 18, 22416-22425

DOI: 10.1039/C6CP02645A

To find out more about what ISIS can tell us about biology, watch Protein Folding and Particle Accelerators: A New Solution. In this short film, Dr Sylvia McLain explains her research into one of the most fundamental questions of life: how water is involved in protein folding. Courtesy of The Royal Institution.