A neurotransmitter prodrug, or neurotransmitter precursor, is a drug that acts as a prodrug of a neurotransmitter. A variety of neurotransmitter prodrugs have been developed and used in medicine. They can be useful when the neurotransmitter itself is not suitable for use as a pharmaceutical drug owing to unfavorable pharmacokinetic or physicochemical properties, for instance high susceptibility to metabolism, short elimination half-life, or lack of bloodâÂÂbrain barrier permeability. Besides their use in medicine, neurotransmitter prodrugs have also been used as recreational drugs in some cases.
Monoamine neurotransmitter prodrugs include the catecholamine precursors and prodrugs <small>L</small>-phenylalanine, <small>L</small>-tyrosine, <small>L</small>-DOPA (levodopa), <small>L</small>-DOPS (droxidopa), dipivefrine (O,O<nowiki>'</nowiki>-dipivalylepinephrine), and dibutepinephrine, as well as the serotonin and melatonin precursors and prodrugs <small>L</small>-tryptophan and <small>L</small>-5-hydroxytryptophan (5-HTP; oxitriptan). Other dopamine prodrugs, including etilevodopa, foslevodopa, melevodopa, XP-21279, DopAmide, DA-Phen, O,O<nowiki>'</nowiki>-diacetyldopamine, O,O<nowiki>'</nowiki>-dipivaloyldopamine, docarpamine, gludopa, and gludopamine, have also been developed. Dopamantine (N-adamantanoyl dopamine) is another possible attempt at a dopamine prodrug. Other serotonin prodrugs have been developed as well, such as the renally-selective <small>L</small>-glutamyl-5-hydroxy-<small>L</small>-tryptophan (glu-5-HTP).
5-HTP is additionally a prodrug of N-methylated tryptamine psychedelic trace amines, such as N-methylserotonin (NMS; norbufotenin) and bufotenin (5-hydroxy-N,N-dimethyltryptamine; 5-HO-DMT). The same is also true of <small>L</small>-tryptophan, which is transformed into tryptamine 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 (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 neurotransmitter prodrugs, "false" or "substitute" neurotransmitter prodrugs, such as ñ-methyltryptophan and ñ-methyl-5-hydroxytryptophan (which are prodrugs of ñ-methylserotonin, a substitute neurotransmitter of serotonin), have also been developed. Analogously, ibopamine and fosopamine are prodrugs of epinine (N-methyldopamine; deoxyepinephrine).
ó-Aminobutyric acid (GABA) prodrugs include progabide and tolgabide. Picamilon 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 (ALR) and aldehyde dehydrogenase (ALDH). 4-Amino-1-butanol is to GABA as 1,4-butanediol (4-hydroxy-1-butanol; 1,4-BD) is to ó-hydroxybutyric acid (GHB) (with 1,4-BD being a well-known prodrug of GHB). The metabolic intermediate ó-aminobutyraldehyde (GABAL) is also converted into GABA.
A number of ó-hydroxybutyric acid (GHB) prodrugs are known. These include 1,4-butanediol (1,4-BD) and ó-butyrolactone (GBL), as well as the metabolic intermediate ó-hydroxybutyraldehyde (GHBAL).
Acetylcholine precursors and prodrugs like choline, phosphatidylcholine (lecithin), citicoline (CDP-choline), and choline alphoscerate (ñ-GPC) are known and have been researched.