L-DOPS

L-DOPS

Systematic (IUPAC) name
(2R,3S)-2-amino-3-(3,4-dihydroxyphenyl)-3-hydroxypropanoic acid
Clinical data
Pregnancy cat.	?
Legal status	Rx-only (not yet approved in the US)
Routes	Oral
Pharmacokinetic data
Bioavailability	90%
Metabolism	hepatic
Half-life	1.5 hours
Excretion	renal
Identifiers
CAS number	23651-95-8
ATC code	None
PubChem	CID 3171
UNII	J7A92W69L7 Y
Chemical data
Formula	C9H11NO5
Mol. mass	213.18734 g/mol
Y(what is this?)  (verify)

L-DOPS (L-threo-dihydroxyphenylserine; Droxidopa; SM-5688) is a psychoactive drug and synthetic amino acid precursor which acts as a prodrug to the neurotransmitters norepinephrine (noradrenaline) and epinephrine (adrenaline).^[1] Unlike norepinephrine and epinephrine themselves, L-DOPS is capable of crossing the protective blood-brain barrier (BBB).^[1]

Indications

• Neurogenic orthostatic hypotension (NOH),^[2] as well as NOH associated with multiple system atrophy (MSA), familial amyloid polyneuropathy (FAP), pure autonomic failure (PAF), and Parkinson's disease (PD).
• Intradialytic hypotension (IDH) or hemodialysis-induced hypotension.
• Hypotension associated with fibromyalgia syndrome (FMS) and chronic fatigue syndrome (CFS).^[3]

History

L-DOPS was developed by Sumitomo Pharmaceuticals under the trade name Droxidopa for the treatment of hypotension, including NOH,^[2] and NOH associated with various disorders such as MSA, FAP, and PD, as well as IDH. The drug has been used in Japan and some surrounding Asian areas for these indications since 1989. Following a merge with Dainippon Pharmaceuticals in 2006, Dainippon Sumitomo Pharma licensed L-DOPS to Chelsea Therapeutics to develop and market it worldwide except in Japan, Korea, China, and Taiwan.

Clinical Trials

Though L-DOPS has been used in Japan and Southeast Asia already for some time, it is also currently in clinical trials at the phase III point in the United States (U.S.), Canada, Australia, and throughout Europe. Provided L-DOPS successfully completes clinical trials, it could be approved for the treatment of NOH as early as 2011.^[4] Additionally, phase II clinical trials for IDH are also underway. Chelsea Therapeutics obtained orphan drug status (ODS) for L-DOPS in the U.S. for NOH, and that of which associated with PD, PAF, and MSA, and is the pharmaceutical company developing it in that country.

Pharmacology

L-DOPS is a prodrug of norepinephrine and epinephrine used to increase the concentrations of these neurotransmitters in the body and brain.^[1] It is metabolized by aromatic L-amino acid decarboxylase (AAAD), also known as DOPA decarboxylase (DDC). Patients with NOH have depleted levels of norepinephrine and epinephrine which leads to decreased blood pressure or hypotension upon orthostatic challenge.^[5] L-DOPS works by increasing the levels of norepinephrine and epinephrine in the peripheral nervous system (PNS), which induces tachycardia or increased heart rate and hypertension or increased blood pressure, thus enabling the body to maintain blood flow upon and while standing.

L-DOPS can also cross the blood-brain barrier (BBB) where it is converted to norepinephrine and epinephrine from within the brain.^[1] Increased levels of norepinephrine and epinephrine in the central nervous system (CNS) may be beneficial to patients in a wide range of indications. L-DOPS can be coupled with a peripheral aromatic L-amino acid decarboxylase inhibitor (AAADI) or DOPA decarboxylase inhibitor (DDC) such as carbidopa (Lodosyn) to increase central norepinephrine and epinephrine concentrations while maintaining peripheral levels.

Side Effects

With close to 20 years on the market, L-DOPS has proven to have very few side effects of which most are mild. Patients have reported tachycardia, hypertension, nausea and vomiting, and headache or migraine.^[2]

See also

• D-DOPA (Dextrodopa)
• L-DOPA (Levodopa; Sinemet, Parcopa, Atamet, Stalevo, Madopar, Prolopa, etc)
• Methyldopa (Aldomet, Apo-Methyldopa, Dopamet, Novomedopa, etc)
• Dopamine (Intropan, Inovan, Revivan, Rivimine, Dopastat, Dynatra, etc)
• Norepinephrine (Noradrenaline; Levophed, etc)
• Epinephrine (Adrenaline; Adrenalin, EpiPed, Twinject, etc)

References

1. ^ ^{a b c d} Goldstein, DS (2006). "L-Dihydroxyphenylserine (L-DOPS): a norepinephrine prodrug". Cardiovasc Drug Rev 24 (3-4): 189–203. doi:10.1111/j.1527-3466.2006.00189.x. PMID 17214596. 
2. ^ ^{a b c} Mathias, Christopher J (2008). "L-dihydroxyphenylserine (Droxidopa) in the treatment of orthostatic hypotension". Clin Auton Res 18 (Supplement 1): 25–29. doi:10.1007/s10286-007-1005-z. 
3. ^ Crofford, LJ (2008). "Pain management in fibromyalgia". Curr Opin Rheumatol 20 (3): 246–250. doi:10.1097/BOR.0b013e3282fb0268. PMID 18388513. 
4. ^ Search of: "Droxidopa" - List Results - ClinicalTrials.gov
5. ^ Robertson, David (2008). "The pathophysiology and diagnosis of orthostatic hypotension". Clin Auton Res 18 (Supplement 1): 2–7. doi:10.1007/s10286-007-1004-0. 

External links

• Chelsea Therapeutics
• Vanderbilt Autonomic Dysfunction Center