anxiety disorders, panic disorder, obsessive-compulsive disorder, phobias, post-traumatic stress disorder

Snail toxin may spur new meds for Alzheimer's, Parkinson's, depression

University of Utah researchers isolated an unusual nerve toxin in an ocean-dwelling snail, and say its ability to glom onto the brain's nicotine receptors may be useful for designing new drugs to treat a variety of psychiatric and brain diseases.

Conus omaria shell

"We discovered a new toxin from a venomous cone snail that may enable scientists to more effectively develop medications for a wide range of nervous system disorders including Parkinson's disease, Alzheimer's disease, depression, nicotine addiction and perhaps even schizophrenia," says J. Michael McIntosh.

Discovery of the new cone snail toxin will be published Friday, Aug. 25 in The Journal of Biological Chemistry by a team led by McIntosh, a University of Utah research professor of biology, professor and research director of psychiatry, member of the Center for Peptide Neuropharmacology and member of The Brain Institute.

McIntosh is the same University of Utah researcher who - as an incoming freshman student in 1979 - discovered another "conotoxin" that was developed into Prialt, a drug injected into fluid surrounding the spinal cord to treat severe pain due to cancer, AIDS, injury, failed back surgery and certain nervous system disorders. Prialt was approved in late 2004 in the United States and was introduced in Europe last month.

McIntosh says he expects it will take 10 to 20 years to develop new medications based on what is learned from the new toxin - named alpha conotoxin OmIA (oh-em-one-ay) - isolated from a cone snail species named Conus omaria, which lives in the Pacific and Indian oceans and eats other snails. It ranges from 30-90 mm long.

McIntosh says the OmIA toxin will be useful in designing new medicines because it fits like a key into certain lock-like "nicotinic acetylcholine receptors" found on nerve cells in the brain and the rest of the nervous system.

"Those are the same types of receptors you activate if you smoke a cigarette," he says, explaining that nicotine in cigarette smoke "binds" to the receptor to trigger the release of a neurotransmitter, which is a chemical that carries a nerve impulse from one nerve cell to another, allowing nerve cells to communicate.

"Nicotine acts on those receptors in our brain, but they are in our brain for better reasons than to enjoy a cigarette," McIntosh says. Different forms or subtypes of nicotinic receptors control the release of different neurotransmitters. "That's important because if you had compounds to facilitate the release of one neurotransmitter and not another neurotransmitter, that opens up medicinal potential," he says.

"For instance, one receptor modifies the release of dopamine. There are inadequate amounts of dopamine in Parkinson's disease," so a medicine designed to fit into a certain subtype of nicotinic receptor would produce more dopamine and thus protect against the development of tremors and other Parkinson's symptoms. Indeed, other studies have found that smoking seems to forestall Parkinson's disease.

"One reason people smoke is they feel their thinking may be a little better, with increased attention and focus," McIntosh says, noting that pharmaceutical companies "would like to mimic that positive benefit without all the downsides of cigarette smoke."

Other nicotinic receptors influence "the release of serotonin and norepinephrine, two neurotransmitters strongly implicated in mood disorders" such as depression, so a drug to activate those receptors might treat depression, he adds.

Schizophrenics tend to smoke heavily because something in cigarette smoke "seems to help them filter out irrelevant stimuli. They can focus better," McIntosh says. So a drug aimed at certain nicotinic receptors might treat schizophrenia.

McIntosh says the new toxin itself is unlikely to become a drug because it blocks rather than stimulates nicotinic receptors. But because it can act on some types of nicotinic receptors and not others - like a key that opens some locks but not others - it has great potential as a tool for precisely identifying the shape and structure of the receptor "locks," thus making it easier to design new medicines or "keys" to fit those receptors and trigger them to release desired neurotransmitters.

In the new study, about 70 compounds from numerous cone snail species were screened in collaboration with Taylor's lab at the University of California, San Diego.

Taylor uses "acetylcholine binding protein" as a model for nicotinic receptors. In other words, cone snail toxin "keys" that fit into nicotinic receptor "locks" also fit into highly similar "locks" made of this binding protein. So the binding protein was used as a way to find toxins that also would fit into nicotinic receptors. The new OmIA toxin was most interesting because it tightly fits some nicotinic receptors but not others. A drug that tightly fits desired receptors but not others is less likely to have undesirable side effects.

Unlike nicotinic receptors, the binding protein can be grown in crystal form, allowing Taylor's team to use X-ray crystallography to make detailed microscopic pictures of how the toxin fit into the binding protein. Meanwhile, Han in South Korea used nuclear magnetic resonance to make pictures showing the structure of the new toxin.

Together, the images provide a highly detailed picture of how the cone snail toxin fits into the binding protein, and thus how it also would fit into a nicotinic receptor.

"By putting the two together, you can get a high-resolution picture of the binding site," says McIntosh. "That allows for rational drug development. It allows you to design compounds that will bind to the same [nicotinic receptor] site, and it allows you to begin to understand how to bind to one receptor subtype and not another" to trigger the release of whatever neurotransmitter is needed to treat or prevent a particular disease.

"It is the picture of the binding site and the ability to distinguish one type of nicotinic receptor from another that makes the toxin so valuable," he adds.

"The whole idea is to make the model of the nicotinic receptor so predictive that you can then really speed up the development of drugs," McIntosh says. "If you have an accurate model of the receptor, you can plug in a model of your drugs and do a lot of 'virtual screening.' Rather than synthesizing a million compounds and having all but one be duds, you can synthesize a few thousand compounds based on the model and come up with a better drug with less time and resources."

The snails from which the new toxin was obtained were collected by divers in Olivera's native Philippines. Venomous snails use a dart-like tooth to zap fish, snails and other prey, injecting them with an immobilizing toxin.

Talley TT, Olivera BM, Han KH, Christensen SB, Dowell C, Tsigelny I, Ho KY, Taylor P, McIntosh JM.
-Conotoxin OmIA Is a Potent Ligand for the Acetylcholine-binding Protein as Well as 3ß2 and 7 Nicotinic Acetylcholine Receptors
J Biol Chem. 2006 Aug 25; 281(34):24678-24686. [Abstract]