Friday, November 25, 2005

Pre-pipeline News

The "pipeline" in drug development refers to those new molecular entities that may soon be markable as pharmaceutical products. Bored physicians looking for something to blog about often peek into the pipeline, knowing that there always is an audience hungry for news about emerging products.

As is happens, I am not particularly bored. Rather, I am inspired, because I am listening to Patti Smith's Legacy Edition of the venerable album, Horses. Suitably energized, I present now the latest information on a potential treatment for drug addiction. Although it appears to work in rats, and is far from entering the pipeline that leads to products for humans, it is an interesting molecule.

Researchers in Canada have crafted a peptide that might turn out to be useful. Unlike most other products proposed as treatments for substance dependence, its mechanism of action is such that it could work regardless of the nature of the dependency. That is, it could work equally well, regardless of the substance to which the patient is addicted.

In addicted rats, cell-to-cell communication is compromised as a result of certain long-term changes at the level of individual neurons. Their research has produced a targeted drug that tricks brain cells into preventing those changes. “We think this is a good candidate for a drug against addiction that has very few side effects,” said Wang, a neuroscientist . Although the initial studies are promising, Wang cautioned that the drug is in the early stages of development and is years away from testing in humans.

During addiction to drugs, cells in the nucleus accumbens—a tiny ball of tissue deep in the brain involved in pleasure and motivation—miscommunicate. Normally, one neuron triggers activity in a neighbor by using neurotransmitters such as glutamate. “This is the 'go' signal,” said Wang. “The receiving cell uses glutamate receptors on its surface to listen to the signal.

But after repeated abuse of a drug, cells in the nucleus accumbens internalize glutamate receptors, compromising their ability to listen to the signals. Earlier research showed that receptor internalization in addicted rats accompanies behavioral sensitization, a model of craving. [...]

The researchers began by building a peptide—a long molecule made from a string of amino acids—with a structure similar to the tail of the glutamate receptor that is anchored inside the cell. In addiction, cellular machinery tugs on this tail, pulling the entire receptor into the cell. Without its business end sticking out into the synapse, or space between neurons, the receptor no longer works.

Wang's peptide tricks the cellular machinery into tugging on it instead of the receptor's tail. “Once it gets inside the neuron, the peptide competes with the receptor for binding to the machinery,” Wang explained. With the cellular machinery otherwise occupied, the glutamate receptors stay on the cell surface, where they continue to receive signals.

Nobody has any way of knowing if this ever will be commercially viable. Despite the caveats, it is a nice piece of work. Even if their peptide is not effective in humans, or not practical for use as a treatment, improved understanding of the neuronal mechanism of drug dependence may lead to a new therapeutic approach, one that is practical, safe, and effective.