A neurotransmitter prodrug, or neurotransmitter precursor, is a

drug A drug is any chemical substance other than a nutrient or an essential dietary ingredient, which, when administered to a living organism, produces a biological effect. Consumption of drugs can be via insufflation (medicine), inhalation, drug i ...

that acts as a

prodrug A prodrug is a pharmacologically inactive medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be ...

of a

neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a Chemical synapse, synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell. Neurotra ...

. A variety of neurotransmitter prodrugs have been developed and used in

medicine Medicine is the science and Praxis (process), practice of caring for patients, managing the Medical diagnosis, diagnosis, prognosis, Preventive medicine, prevention, therapy, treatment, Palliative care, palliation of their injury or disease, ...

. They can be useful when the neurotransmitter itself is not suitable for use as a

pharmaceutical drug Medication (also called medicament, medicine, pharmaceutical drug, medicinal product, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy ( pharmacotherapy) is an important part of the ...

owing to unfavorable

pharmacokinetic Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to describing how the body affects a specific subs ...

physicochemical Physical chemistry is the study of macroscopic and microscopic phenomena in chemical systems in terms of the principles, practices, and concepts of physics such as motion, energy, force, time, thermodynamics, quantum chemistry, statistical mecha ...

properties, for instance high susceptibility to

metabolism Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...

, short

elimination half-life Biological half-life (elimination half-life, pharmacological half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the blood plasma. ...

, or lack of

blood–brain barrier The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that regulates the transfer of solutes and chemicals between the circulatory system and the central nervous system ...

permeability. Besides their use in medicine, neurotransmitter prodrugs have also been used as

recreational drug Recreational drug use is the use of one or more psychoactive drugs to induce an altered state of consciousness, either for pleasure or for some other casual purpose or pastime. When a psychoactive drug enters the user's body, it induces an Sub ...

s in some cases.

Monoamine prodrugs

Monoamine neurotransmitter prodrugs include the

catecholamine A catecholamine (; abbreviated CA), most typically a 3,4-dihydroxyphenethylamine, is a monoamine neurotransmitter, an organic compound that has a catechol (benzene with two hydroxyl side groups next to each other) and a side-chain amine. Cate ...

precursors and prodrugs L-phenylalanine, L-tyrosine, L-DOPA (levodopa), L-DOPS (droxidopa),

dipivefrine Dipivefrine, or dipivefrin, also known as epinephrine pivalate and sold under the brand name Propine among others, is a sympathomimetic medication which is used in the treatment of open-angle glaucoma.Dipivefrin . It is available as a 0.1% o ...

(''O'',''O'''-dipivalylepinephrine), and dibutepinephrine, as well as the

serotonin Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...

and

melatonin Melatonin, an indoleamine, is a natural compound produced by various organisms, including bacteria and eukaryotes. Its discovery in 1958 by Aaron B. Lerner and colleagues stemmed from the isolation of a substance from the pineal gland of cow ...

precursors and prodrugs L-tryptophan and L-5-hydroxytryptophan (5-HTP; oxitriptan). Other dopamine prodrugs, including

etilevodopa Etilevodopa (developmental code name TV-1203) is a dopaminergic agent which was developed as a treatment for Parkinson's disease. It is the ethyl ester of levodopa Levodopa, also known as L-DOPA and sold under many brand names, is a dopami ...

foslevodopa Foslevodopa is a medication which acts as a prodrug for levodopa, originally invented in the 1980s but not developed for medical use at that time. It is approved for use in a subcutaneous infusion as a fixed-dose combination with foscarbidopa ...

melevodopa Melevodopa, also known as levodopa methyl ester (LDME) and sold under the brand name Levomet, is a dopaminergic agent. It is the methyl ester of levodopa. It is used in oral tablet form as an effervescent prodrug with 250times the water solubil ...

XP-21279 XP-21279 is a sustained-release levodopa (L-DOPA) prodrug and hence a dopamine precursor and non-selective dopamine receptor agonist which was under development for the treatment of Parkinson's disease. It is taken by mouth. Pharmacology Th ...

DopAmide DopAmide, or L-DopAmide, is a synthetic levodopa (L-DOPA) analogue that can serve as a levodopa and dopamine prodrug and is of potential interest in the treatment of Parkinson's disease. DopAmide has an amide rather than the carboxyl group of L- ...

DA-Phen DA-Phen, also known as dopamine–phenylalanine conjugate, is a synthetic dopamine prodrug which is under preclinical evaluation. Dopamine itself is hydrophilic and is unable to cross the blood–brain barrier, thus showing peripheral selectivi ...

, ''O'',''O'''-diacetyldopamine, ''O'',''O'''-dipivaloyldopamine, docarpamine, gludopa, and gludopamine, have also been developed.

Dopamantine Dopamantine (, ; developmental code name SCH-15507; also known as ''N''-adamantanoyl dopamine) is an antiparkinsonian drug of the adamantane group that developed for treatment of Parkinson's disease but was never marketed. It was developed and ...

(''N''-adamantanoyl dopamine) is another possible attempt at a dopamine prodrug. Other serotonin prodrugs have been developed as well, such as the

renally In humans, the kidneys are two reddish-brown bean-shaped blood-filtering organs that are a multilobar, multipapillary form of mammalian kidneys, usually without signs of external lobulation. They are located on the left and right in the retrope ...

-selective L-glutamyl-5-hydroxy-L-tryptophan (glu-5-HTP). 5-HTP is additionally a prodrug of ''N''-

methylated Methylation, in the chemical sciences, is the addition of a methyl group on a substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replacing a hydrogen atom. These term ...

tryptamine Tryptamine is an indolamine metabolite of the essential amino acid tryptophan. The chemical structure is defined by an indole—a fused benzene and pyrrole ring, and a 2-aminoethyl group at the second carbon (third aromatic atom, with the firs ...

psychedelic Psychedelics are a subclass of hallucinogenic drugs whose primary effect is to trigger non-ordinary mental states (known as psychedelic experiences or "trips") and a perceived "expansion of consciousness". Also referred to as classic halluci ...

trace amine Trace amines are an endogenous group of trace amine-associated receptor 1 (TAAR1) agonists – and hence, monoaminergic neuromodulators – that are structurally and metabolically related to classical monoamine neurotransmitters. Compared to ...

s, such as ''N''-methylserotonin (NMS; norbufotenin) and

bufotenin Bufotenin, also known as dimethylserotonin or as 5-hydroxy-''N'',''N''-dimethyltryptamine (5-HO-DMT), is a serotonergic psychedelic of the tryptamine family. It is a derivative of the psychedelic dimethyltryptamine (DMT) and of the neurotransmi ...

(5-hydroxy-''N'',''N''-dimethyltryptamine; 5-HO-DMT). The same is also true of L-tryptophan, which is transformed into

as well as into ''N''-methyltryptamine (NMT) and ''N'',''N''-dimethyltryptamine (''N'',''N''-DMT). Dependent on these transformations, both tryptophan and 5-HTP produce the

head-twitch response The head-twitch response (HTR), also sometimes known as wet dog shakes (WDS) in rats, is a rapid side-to-side head movement that occurs in mice and rats in association with serotonin 5-HT2A receptor activation. Serotonergic psychedelics like lys ...

(HTR), a behavioral proxy of psychedelic effects, at sufficiently high doses in animals. ''O''-Acetylbufotenine and ''O''-pivalylbufotenine are thought to be centrally active prodrugs of the peripherally selective bufotenin. Although they are not

endogenous Endogeny, in biology, refers to the property of originating or developing from within an organism, tissue, or cell. For example, ''endogenous substances'', and ''endogenous processes'' are those that originate within a living system (e.g. an ...

neurotransmitter prodrugs, "false" or "substitute" neurotransmitter prodrugs, such as α-methyltryptophan and

α-methyl-5-hydroxytryptophan α-Methyl-5-hydroxytryptophan (α-Me-5-HTP) is a synthetic compound, synthetic substituted tryptamine, tryptamine chemical derivative, derivative, an artificial amino acid, and a prodrug of α-methylserotonin. It is the α-methyl group, methyla ...

(which are prodrugs of α-methylserotonin, a substitute neurotransmitter of serotonin), have also been developed. Analogously, ibopamine and fosopamine are prodrugs of

epinine Deoxyepinephrine, also known by the common names ''N''-methyldopamine and epinine, is an organic compound and natural product that is structurally related to the important neurotransmitters dopamine and epinephrine. All three of these compounds a ...

(''N''-methyldopamine; deoxyepinephrine).

GABA prodrugs

γ-Aminobutyric acid GABA (gamma-aminobutyric acid, γ-aminobutyric acid) is the chief inhibitory neurotransmitter in the developmentally mature mammalian central nervous system. Its principal role is reducing neuronal excitability throughout the nervous system. GA ...

(GABA) prodrugs include

progabide Progabide ( INN; trade name Gabrene, Sanofi-Aventis) is an analogue and prodrug of γ-aminobutyric acid (GABA) used in the treatment of epilepsy. Via conversion into GABA, progabide behaves as an agonist of the GABAA, GABAB, and GABAA-ρ ...

and tolgabide.

Picamilon Picamilon (also known as ''N''-nicotinoyl-GABA, pycamilon, and pikamilon) is a drug formed by a synthetic combination of niacin and γ-aminobutyric acid (GABA). It was developed in the Soviet Union in 1969 and further studied in both Russia and ...

has been claimed to be a prodrug of GABA, but has not actually been demonstrated to be converted into GABA. Pivagabine was once thought to be a prodrug of GABA, but this proved not to be the case. 4-Amino-1-butanol is known to be converted into GABA through the actions of

aldehyde reductase In enzymology, aldose reductase (or aldehyde reductase) () is an enzyme in humans encoded by the gene AKR1B1. It is an cytosolic NADPH-dependent oxidoreductase that catalyzes the reduction of a variety of aldehydes and carbonyls, including monos ...

(ALR) and

aldehyde dehydrogenase Aldehyde dehydrogenases () are a group of enzymes that catalyse the oxidation of aldehydes. They convert aldehydes (R–C(=O)) to carboxylic acids (R–C(=O)). The oxygen comes from a water molecule. To date, nineteen ALDH genes have ...

(ALDH). 4-Amino-1-butanol is to GABA as 1,4-butanediol (4-hydroxy-1-butanol; 1,4-BD) is to

γ-hydroxybutyric acid γ-Hydroxybutyric acid, also known as ''gamma''-hydroxybutyric acid, GHB, or 4-hydroxybutanoic acid, is a naturally occurring neurotransmitter and a depressant, depressant drug. It is a precursor to GABA, glutamate, and glycine in certain brai ...

(GHB) (with 1,4-BD being a well-known prodrug of GHB). The

metabolic intermediate Metabolic intermediates are compounds produced during the conversion of substrates (starting molecules) into final products in biochemical reactions within cells. Although these intermediates are of relatively minor direct importance to cell ...

γ-aminobutyraldehyde 4-Aminobutanal, also known as γ-aminobutyraldehyde, 4-aminobutyraldehyde, or GABA aldehyde, is a metabolite of putrescine and a biological precursor of γ-aminobutyric acid (GABA). It can be converted into GABA by the actions of diamine oxidas ...

(GABAL) is also converted into GABA.

GHB prodrugs

A number of

(GHB) prodrugs are known. These include 1,4-butanediol (1,4-BD) and

γ-butyrolactone γ-Butyrolactone (GBL) or ''gamma''-butyrolactone is an organic compound with the formula . It is a hygroscopic, colorless, water-miscible liquid with a weak characteristic odor. It is the simplest Γ-lactone, 4-carbon lactone. It is mainly used ...

(GBL), as well as the

γ-hydroxybutyraldehyde (GHBAL).

Acetylcholine prodrugs

Acetylcholine Acetylcholine (ACh) is an organic compound that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Par ...

precursors and prodrugs like

choline Choline is a cation with the chemical formula . Choline forms various Salt (chemistry), salts, such as choline chloride and choline bitartrate. An essential nutrient for animals, it is a structural component of phospholipids and cell membrane ...

phosphatidylcholine Phosphatidylcholines (PC) are a class of phospholipids that incorporate choline as a headgroup. They are a major component of biological membranes and can easily be obtained from a variety of readily available sources, such as egg yolk or soyb ...

(

lecithin Lecithin ( ; from the Ancient Greek "yolk") is a generic term to designate any group of yellow-brownish fatty substances occurring in animal and plant tissues which are amphiphilic – they attract both water and fatty substances (and so ar ...

citicoline Citicoline (INN), also known as cytidine diphosphate-choline (CDP-choline) or cytidine 5'-diphosphocholine is an intermediate in the generation of phosphatidylcholine from choline, a common biochemical process in cell membranes. Citicoline is natu ...

(CDP-choline), and choline alphoscerate (α-GPC) are known and have been researched.

References

{{Neurotransmitter metabolism intermediates Neurotransmitter precursors Neurotransmitters Prodrugs