New anti-addiction compound shows promise for drug addicts

A new class of compound that acts on the kappa opioid receptors in the brain is offering hope as Wellington researchers look for anti-addiction drugs with fewer side effects.

Dr Bronwyn Kivell, a senior lecturer in neurobiology in the School of Biological Sciences at Victoria University of Wellington, has been working on the this new class of compound as part of a study funded by the Health Research Council of New Zealand (HRC). She says compounds that act on the receptors were first identified as having anti-addiction effects in the 1990s, but issues with side effects stopped them going through clinical development.

"Since then, a new class of compound (Salvinorin-A) that has a completely different structure but activates the kappa opioid receptor has been discovered, and we believe it has less side effects than the traditional compounds," says Dr Kivell.

Side effects often involve unpleasant dysphotric feelings, Dr Kivell explains: "These unpleasant feelings can be quite aversive, so people don't want to take them, which is not ideal for pharmacotherapy. There are also potential motor deficits, such as sedation, leaving people sleepy."

She is working closely with medicinal chemist colleague Professor Thomas Prisinzano who makes the new, more bioavailable compounds for testing.

"Compounds that have anti-addiction effects get tested through a whole battery of side effect profiles such as sedation and aversion. We have found that all the side effects, except possibly depression, are not there," says Dr Kivell.

They are now trying to understand better the link between addiction and mood.

"These are complex behaviours. Addiction is not just a simple thing you turn on and off. It involves memory, impulse, mood and other behaviours – it's very complex."

Dr Kivell says all drugs of abuse modulate the dopamine pathway in the brain. The kappa opioid receptors are in the same place as what are known as the dopamine transporters and they have as yet unpublished evidence now that they actually regulate the function of these transporters.

"We can directly show that these increase the effectiveness of the dopamine transporter, which means it reduces the amount of reward the drugs have. The dopamine is cleared away faster and repackaged so it's not there causing the reward effects. It removes the high so the recreational drug does not have as much of an effect."

They have several promising candidates within the Salvinorin-A class of compounds. One of the interesting aspects of these new drugs is that if they are too potent the side effects are present, but if they are less potent then they are likely to have fewer side effects.

Dr Kivell says the next step is to try out compounds that are less potent.

"We've worked out how much activation of the kappa opioid receptor is required for the anti-addiction effect, so once we know the characteristics of the compounds, we kind of know what will work. We know what the right dosing is before we start which makes the whole process a lot easier and a lot faster to go through the next battery of compounds."

New data shows that Salvinorin-A also has anti-depressant effects.

"We believe we can get rid of the depressive effects but keep the anti-addiction effects. Mood is really important in addiction, particularly depression which plays a part in relapse."

Dr Kivell says there are two major points in the addiction pathway where therapeutic drugs can target. What they are working on now is the “stopping addiction point” by removing the reward from the drugs. The other point involves “stopping relapse” because about 80 per cent of recovering addicts will relapse at some stage in their life.

"Stress and depression are predisposing factors for addicts to relapse, and we think the kappa system can be modulated to reduce depression in those stages of the addiction cycle as well."

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