Technology ID

Synthesis and use of deuterated L-DOPS to treat norepinephrine deficiency

Lead Inventor
Goldstein, David (National Institute of Neurological Disorders and Stroke)
Sullivan, Patricia (National Institute of Neurological Disorders and Stroke)
Holmes, Courtney (National Institute of Neurological Disorders and Stroke)
Schneider, Frannk (CDRD Berolina AB)
Therapeutic Areas
Infectious Disease
Lead IC
This invention relates to the synthesis and methods of using a drug, deuterated L-DOPS, to treat deficiencies in the neurotransmitter norepinephrine. This classic neurotransmitter has roles in both the brain and the periphery. In the brain, norepinephrine is thought to play important roles in attention, memory, sleep, pain, movement, distress, and mood. Outside the brain, norepinephrine mediates regulation of the circulation by the sympathetic nervous system by increasing blood pressure.

Oral norepinephrine is ineffective in treating deficiencies because the gut-blood and blood-brain barriers effectively block this neurotransmitter from crossing. A norepinephrine pro-drug (L-DOPS, droxidopa, Northera) is being developed for treating deficiencies of norepinephrine. While L-DOPS can induce the synthesis of norephinephrine, the produced neurotransmitter is rapidly degraded into toxic byproducts. Substituting deuterium for the hydrogen in L-DOPS, deuterated L-DOPS, decreases the ability of the synthesized norepinephrine from being degraded.
Commercial Applications
Deuterated L-DOPS may prove useful for treating any of a variety of forms of norepinephrine deficiency. A New Drug Application to the US FDA has been filed by Chelsea Therapeutics for L-DOPS (brand-name Northera) to treat symptomatic orthostatic hypotension.

Competitive Advantages
Norepinephrine generated from L-DOPS undergoes substantial degradation by the enzyme monoamine oxidase. The immediate product of the oxidative deamination is an aldehyde, dihydroxyphenylglycolaldehyde, which is toxic. Deuterium substitution at the alpha carbon of catecholamines decreases susceptibility to monoamine oxidase. Therefore, deuterated L-DOPS should be more effective and less toxic than non-deuterated L-DOPS in treating norepinephrine deficiency states.
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