Nitrogen Not Required for Brain Drugs

Researchers have needlessly limited themselves in the search for new drugs by following an assumption that may not be correct, according to a new study authored by a Harvard professor.

In the past, efforts to discover drugs for use in the brain have been governed by the assumption that any such chemical compound needed to contain a nitrogen atom. As a result, all current drugs which target the brain have nitrogen atoms.

But a study by Bertha K. Madras, associate professor of psychobiology at Harvard Medical School, reveals that nitrogen is not a required element of drugs working in the brain.

Madras and her co-authors found a group of drugs without nitrogen that recognizes the same molecular targets as nitrogen-containing drugs.

These experimental drugs also appear to be as powerful as the ones that contain nitrogen.

"This study has literally shredded an old premise," Madras said in a statement. "It forces a revision of current concepts of drug binding domains."

Madras suggested in the study that the results are significant because they may potentially lead to better treatments for depression, cocaine addiction and attention deficit hyperactivity disorder (ADHD).

The results may also help scientists find other natural compounds in the brain that they did not previously know how to look for, according to Madras.

The study was published in this month's issue of the journal Synapse.

Madras said she did not set out to test the assumption that nitrogen is required for all compounds designed for use in the brain. Rather, she was trying to find a treatment for cocaine addiction.

Cocaine acts by blocking a dopamine transporter, which attempts to remove a neurotransmitter from a synaptic gap in the brain to prevent overstimulation.

Madras attempted in her research to find a drug that would block the action of cocaine and leave the dopamine transporter untouched.

By replacing the nitrogen atom with an oxygen atom, researchers found that the new compounds bound specifically to dopamine transporters as well as other transporters in the brain such as serotonin and norepinephrine.

The new compounds were also about as potent as current drugs.

One of the new compounds, called tropoxane, recognized the dopamine transporter with higher potency then cocaine or Ritalin, a commonly-prescribed drug to treat ADHD.

Researchers also reported that the new compounds bind the serotonin transporter with potencies similar to Prozac and other antidepressants.

Madras said she thinks the new compounds will do more than just bind to the target; they will actually affect the function as well.

The experimental compounds blocked dopamine transport in experiments with cell cultures, according to the study.

Preliminary tests with living animals also indicated that the compounds produce bio-chemical and behavioral affects comparable to those of other dopamine transporter blockers.

Researchers can benefit from her data, Madras suggests, because it is unnecessary for drugs to act in the same way as neuro-transmitters.

Neurotransmitters cross the synaptic gaps in the brain in milliseconds, stimulate the neuron on the other side and are then metabolized quickly.

Nitrogen is necessary to give neurotransmitters the ability to carry out these steps.

But drugs do not have to act in the same way and a slower mode of action might lead to a longer-lasting drug that would prevent the patient from having to take medicine every few hours.

According to Madras, the results suggest that there may be a different mechanism by which drugs recognize targets in the brain that had previously been overlooked.

Previous assumptions operated under the theory that the nitrogen atom forms a strong ionic bond with a counterion on the brain's target molecule.

However, the new results suggest that the experimental drugs, and possibly other compounds as well, bind to transporters by aligning the fatty parts of their structure with similar fatty components on the transporter through what is known as molecular stacking interaction.

Madras said the potential of the new drugs is unclear because much work remains to study the toxicology and pharmacology of the new compounds.

"I feel that we opened a small window in a dark house and see that there is a whole new vista," Madras said in the statement "And now, let's walk and see how far that takes us."