Neurotransmitter prodrug

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.^[1][2] 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 blood–brain barrier permeability.^[1][2][3] Besides their use in medicine, neurotransmitter prodrugs have also been used as recreational drugs in some cases.^[4][5]

Levodopa (L-DOPA), a prodrug of dopamine which is used to treat Parkinson's disease and certain other conditions.

Monoamine prodrugs

Main article: Monoamine precursor

Monoamine neurotransmitter prodrugs include the catecholamine precursors and prodrugs L-phenylalanine, L-tyrosine, L-DOPA (levodopa), L-DOPS (droxidopa), dipivefrine (O,O'-dipivalylepinephrine), and dibutepinephrine,^[1][3] as well as the serotonin and melatonin precursors and prodrugs L-tryptophan and L-5-hydroxytryptophan (5-HTP; oxitriptan).^[6][7][8] Other dopamine prodrugs, including etilevodopa, foslevodopa, melevodopa, XP-21279, DopAmide, DA-Phen, O,O'-diacetyldopamine, O,O'-dipivaloyldopamine, docarpamine, gludopa, and gludopamine, have also been developed.^{[9][10][11][12][13]} Dopamantine (N-adamantanoyl dopamine) is another possible attempt at a dopamine prodrug.^[14][15] Other serotonin prodrugs have been developed as well, such as the renally-selective L-glutamyl-5-hydroxy-L-tryptophan (glu-5-HTP).^[16][17][18]

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).^{[19][20][21][22][23]} The same is also true of L-tryptophan, which is transformed into tryptamine as well as into N-methyltryptamine (NMT) and N,N-dimethyltryptamine (N,N-DMT).^{[20][24][25][26][27]} 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.^{[20][28][29][21][30][19]} O-Acetylbufotenine and O-pivalylbufotenine are thought to be centrally active prodrugs of the peripherally selective bufotenin.^[31][32][33]

Although they are not endogenous neurotransmitter prodrugs, "false" or "substitute" neurotransmitter prodrugs, such as α-methyltryptophan and α-methyl-5-hydroxytryptophan (which are prodrugs of α-methylserotonin, a substitute neurotransmitter of serotonin), have also been developed.^[34] Analogously, ibopamine and fosopamine are prodrugs of epinine (N-methyldopamine; deoxyepinephrine).^[35]

GABA prodrugs

γ-Aminobutyric acid (GABA) prodrugs include progabide and tolgabide.^[2][36] Picamilon has been claimed to be a prodrug of GABA, but has not actually been demonstrated to be converted into GABA.^[37][38] Pivagabine was once thought to be a prodrug of GABA, but this proved not to be the case.^[39]

4-Amino-1-butanol is known to be converted into GABA through the actions of aldehyde reductase (ALR) and aldehyde dehydrogenase (ALDH).^[40] 4-Amino-1-butanol is to GABA as 1,4-butanediol (4-hydroxy-1-butanol; 1,4-BD) is to γ-hydroxybutyric acid (GHB) (with 1,4-BD being a well-known prodrug of GHB).^[40][41] The metabolic intermediate γ-aminobutyraldehyde (GABAL) is also converted into GABA.^[42][43]

GHB prodrugs

A number of γ-hydroxybutyric acid (GHB) prodrugs are known.^[4] These include 1,4-butanediol (1,4-BD) and γ-butyrolactone (GBL), as well as the metabolic intermediate γ-hydroxybutyraldehyde (GHBAL).^{[4][5][41][44]}

Acetylcholine prodrugs

Acetylcholine precursors and prodrugs like choline, phosphatidylcholine (lecithin), citicoline (CDP-choline), and choline alphoscerate (α-GPC) are known and have been researched.^[45]