Breaking the tension – new directions in schizophrenia research

Dr Daniel Scott is digging through old pharmaceutical tailings, determined to unearth overlooked nuggets in the search for new schizophrenia treatments.

While he’s unlikely to find gold, he’d be very happy to discover a neuropeptide – small proteins used by neurons to communicate with each other. “Neuropeptides were a hot topic in big pharmaceutical companies for decades,” says Dr Daniel Scott, head of the Florey’s Receptor Structure and Drug Discovery Laboratory.

“Unfortunately, when the big pharmas tested neuropeptides in the lab, a range of side-effects led to many clinical trial failures in areas like depression. As a result, large scale commercial drug discovery for psychiatric diseases has stalled.

When the pharmaceutical industry decides to walk away, it leaves a space which is often filled by nimble academics working in not-for-profit institutes like the Florey.

“There is the possibility of finding an absolute treasure trove of new drug targets for devastating conditions like schizophrenia. About one per cent of Australians are affected, but schizophrenia has a hugely disproportionate societal and financial impact, in the order of billions of dollars every year.”

Dan believes he may be about to hit a rich seam with a molecule called neurotensin, and its receptor NTS1.

Untreated patients with schizophrenia have lower neurotensin levels in their spinal fluid, and the lower the level, the worse their symptoms. After standard antipsychotic treatment, neurotensin levels increase in patients’ brains.

“This gives us a pretty strong clue that drugs that activate the receptor directly, or enhance signalling, could be used to treat schizophrenia,” says Dan.

But the pickings in this field aren’t easy. Drug companies haven’t been able to find an artificial drug and have only managed to create short proteins to activate the receptor. The problem with these is that the molecules are large and therefore unable to penetrate into the brain where they need to work.

Dan thinks he’s cracked the problem though, by examining the neurotensin receptor in unprecedented detail, almost down to the atomic scale.

“A few years ago, we used X-rays to probe neurotensin receptor crystals to solve its molecular structure. This gave us a beautiful picture, but it’s just a snapshot. It doesn’t reflect the intricate, complicated dance that happens in a working brain.

I have a fantastic collaboration with Associate Professor Paul Gooley at Bio21, using a technique called nuclear magnetic resonance spectroscopy to directly probe the molecular movements that occur when neurotensin binds its receptor.

“Using this technique, we saw that neurotensin continues to wiggle around when bound to its receptor, and this movement may be vital for turning the pathway from off to on. So now we know what a small molecule drug needs to do at the atomic scale, we can crack on with designing one that mimics the stimulating action of neurotensin.

“This sort of basic research will allow us to design small molecules that will let us validate neurotensin as a schizophrenia target, as suggested by animal and clinical studies and may lead to new clinical trials.”

This story demonstrates the extraordinary complexity of research involving the minutiae of brain function. Searching for a speck of gold in a pan seems simple by comparison.