Sir James W. Black, M.D., F.R.S., the recipient of the 1988 Nobel Prize for Medicine once said, "The easiest way to find a drug is to start with one." Avanir Pharmaceuticals, Inc. and Concert Pharmaceuticals, Inc. appear to subscribe to Black's view as they have recently announced an exclusive license agreement that gives Avanir worldwide rights to develop and commercialize Concert's deuterium-modified cough suppressant - dextromethorphan (d-DXM) - for the potential treatment of neurological and psychiatric disorders.

Since the discovery of deuterium in 1934, its biological effects have been extensively studied. One of every 6,400 hydrogen atoms is actually deuterium - a hydrogen isotope whose nucleus contains a proton and a neutron. (The nucleus of protium, the more common hydrogen isotope, only contains a proton.)

Hydrogen atom and its heavier isotopes (Image: NASA)

Usually, changing the isotopes of which a chemical is composed has very little effect on the chemical reactivity, as the size, shape, and electronic structure of the chemical are only slightly altered.

When hydrogen is exchanged for deuterium, however, changes in chemistry and chemical reaction rates are more profound. For example, the excitation energy of a deuterium-carbon bond is about 33 percent larger than that for a protium-carbon bond. This results in roughly a sixfold reduction in reaction rate at room temperature - clearly sufficient to change the complex unfolding of hydrogen chemistry in the human body.

Addition of heavy water to the diet of animals ranging from protozoa to hamsters universally slows their circadian cycles by as much as a dose-dependent 10 percent. The reduced reaction rate of deuterated compounds has been suggested for use in extension of life, despite observations that mammals whose water source was more than 30 percent heavy water eventually died of its metabolic effects.

Attempts to alter the target and/or duration of drug-induced effects through deuteration have been ongoing for decades. As early as 1961, chemists reported attempting to lengthen morphine's duration of action through deuteration aimed at slowing its oxidation in the body. They succeeded, but in doing so also slowed the formation of morphine's active metabolite, thereby reducing the drug's effectiveness.

Dextromethorphan (DXM)

Dextromethorphan (DXM) is a cough suppressant developed following WWII during CIA-funded research aimed at seeking a less addictive substitute for codeine. While structurally similar to certain opiates, DXM does not act as an opioid receptor agonist, and so does not exhibit conventional opiate activity. There is increasing data suggesting that DXM is a good candidate for the treatment of neurological and psychiatric disorders.

Avanir has been investigating a mixture of DXM and quinidine as a treatment for pseudobulbar affect (PBA), a neurological disorder characterized by sudden, inappropriate, and unpredictable outbursts of crying, laughing, or anger and irritability unassociated with the emotions being experienced by the patient. PBA is typically associated with stroke, multiple sclerosis, or Parkinson's disease, and strongly enhances the patient's urge toward social isolation.

DXM is active against PBA, but is too quickly metabolized to maintain stable therapeutic blood levels. The role of quinidine in the combination is to inhibit the activity of the cytochrome P450 enzyme (CP450), which controls the main route toward metabolizing DXM. This produces a longer effective serum half-life, and with it a controllable effect on PBA. However, there still exists concern about the rather extreme side effects of quinidine, as well as its ability to change the metabolism of many other drugs.

The Avanir/Concert license grants Avanir the right to investigate a series of deuterium-modified DXM molecules (d-DXMs) for stable activity against PBA and other neurological/psychological disorders without requiring co-administration of a CP450 inhibitor. Concert will receive an upfront payment and milestone payments on the course toward FDA approval, as well as tiered royalties on worldwide sales of d-DXM pharmaceuticals. Avanir will take point on research, development, and commercialization of d-DXM pharmaceuticals, while Concert will support Avanir's efforts through development of additional d-DXM candidates.

Hopefully the Avanir/Concert alliance will encourage investigation of other deuterated drugs whose non-deuterated forms are also limited by CP-450 activity.

View gallery - 2 images