Neurotransmitter prodrug

A prodrug of a neurotransmitter

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

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 susceptibility to metabolism 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]

## Monoamine prodrugs

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Main article: Monoamine precursor

Monoamine neurotransmitter prodrugs include the catecholamine precursors and prodrugs L-DOPA (levodopa), L-DOPS (droxidopa), and dipivefrine,[1][3] as well as the serotonin precursor and prodrug L-5-hydroxytryptophan (5-HTP; oxitriptan).[6][7][8] Other dopamine prodrugs, including etilevodopa, foslevodopa, and melevodopa, have also been developed.[9][10] Dopamantine is another possible attempt at a dopamine prodrug.[11][12] Other serotonin prodrugs have been developed as well, such as L-glutamyl-5-hydroxy-L-tryptophan (glu-5-HTP).[13][14][15]

## GABA prodrugs

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γ-Aminobutyric acid (GABA) prodrugs include progabide and tolgabide.[2][16] Picamilon has been claimed to be a prodrug of GABA, but has not actually been demonstrated to be converted into GABA.[17][18] Pivagabine was once thought to be a prodrug of GABA, but this proved not to be the case.[19]

4-Amino-1-butanol is known to be converted into GABA through the actions of aldehyde reductase (ALR) and aldehyde dehydrogenase (ALDH).[20] 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).[20][21] The metabolic intermediate γ-aminobutyraldehyde (GABAL) is also converted into GABA.[22][23]

## GHB prodrugs

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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-aminobutyraldehyde (GHBAL).[4][5][21][24]

## Acetylcholine prodrugs

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Acetylcholine precursors and prodrugs like choline, phosphatidylcholine (lecithin), citicoline (CDP-choline), and choline alphoscerate (α-GPC) are known and have been researched.[25]

## References

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1. ^ a b c Vytla D, Combs-Bachmann RE, Hussey AM, McCarron ST, McCarthy DS, Chambers JJ (May 2012). "Prodrug approaches to reduce hyperexcitation in the CNS". Adv Drug Deliv Rev. 64 (7): 666–685. doi:10.1016/j.addr.2011.11.007. PMID 22138074.
2. ^ a b c Jana S, Mandlekar S, Marathe P (2010). "Prodrug design to improve pharmacokinetic and drug delivery properties: challenges to the discovery scientists". Curr Med Chem. 17 (32): 3874–3908. doi:10.2174/092986710793205426. PMID 20858214.
3. ^ a b Huttunen KM, Raunio H, Rautio J (September 2011). "Prodrugs--from serendipity to rational design". Pharmacol Rev. 63 (3): 750–771. doi:10.1124/pr.110.003459. PMID 21737530.
4. ^ a b c Ponce, Julio de Carvalho (2024). "The use of prodrugs as drugs of abuse". WIREs Forensic Science. 6 (3). doi:10.1002/wfs2.1514. ISSN 2573-9468.
5. ^ a b Trombley TA, Capstick RA, Lindsley CW (December 2020). "DARK Classics in Chemical Neuroscience: Gamma-Hydroxybutyrate (GHB)". ACS Chem Neurosci. 11 (23): 3850–3859. doi:10.1021/acschemneuro.9b00336. PMID 31287661.
6. ^ Maffei ME (December 2020). "5-Hydroxytryptophan (5-HTP): Natural Occurrence, Analysis, Biosynthesis, Biotechnology, Physiology and Toxicology". Int J Mol Sci. 22 (1): 181. doi:10.3390/ijms22010181. PMC 7796270. PMID 33375373.
7. ^ Dörwald, F.Z. (2012). Lead Optimization for Medicinal Chemists: Pharmacokinetic Properties of Functional Groups and Organic Compounds. Wiley. p. 159\. ISBN 978-3-527-33226-7. Retrieved 9 September 2024.
8. ^ Turner EH, Loftis JM, Blackwell AD (March 2006). "Serotonin a la carte: supplementation with the serotonin precursor 5-hydroxytryptophan". Pharmacol Ther. 109 (3): 325–338. doi:10.1016/j.pharmthera.2005.06.004. PMID 16023217.
9. ^ Gupta HV, Lyons KE, Pahwa R (September 2019). "Old Drugs, New Delivery Systems in Parkinson's Disease". Drugs Aging. 36 (9): 807–821. doi:10.1007/s40266-019-00682-9. PMID 31161581.
10. ^ Lees A, Tolosa E, Stocchi F, Ferreira JJ, Rascol O, Antonini A, Poewe W (January 2023). "Optimizing levodopa therapy, when and how? Perspectives on the importance of delivery and the potential for an early combination approach". Expert Rev Neurother. 23 (1): 15–24. doi:10.1080/14737175.2023.2176220. PMID 36729395.
11. ^ Lamoureux G, Artavia G (2010). "Use of the adamantane structure in medicinal chemistry". Current Medicinal Chemistry. 17 (26): 2967–2978. doi:10.2174/092986710792065027. PMID 20858176. "Dopamantine 4, the anti-Parkinson drug which has passed clinical trials, is also based on the ability of adamantane to change the distribution of a drug [10]. The conjugation of an adamantyl group as a "lipophilic carrier" allows poorly absorbed drugs to penetrate the BBB more readily and increase the concentration in the brain tissue."
12. ^ Vernier VG, du Pont EI (1974). "Chapter 3. Antiparkinsonism Drugs". Annual Reports in Medicinal Chemistry. Vol. 9\. Elsevier. pp. 19–26. doi:10.1016/s0065-7743(08)61424-4. ISBN 978-0-12-040509-1. "Carmantadine (VII, Sch 15427) is structurally related to amantadine33. It shares some of its pharmacological actions, was effective in a head-turning test34, and is in early clinical trials. Dopamantine (VIII) combined elements of both amantadine and dopamine in its structure, shares some pharmacological effects of amantadine and is in early clinical trials35."
13. ^ Thorré, Katrien; Sarre, S.; Twahirwa, E.; Meeusen, R.; Ebinger, G.; Haemers, A.; Michotte, Y. (1996). "Effect of l-tryptophan, l-5-hydroxytryptophan and l-tryptophan prodrugs on the extracellular levels of 5-HT and 5-HIAA in the hippocampus of the rat using microdialysis". European Journal of Pharmaceutical Sciences. 4 (4): 247–256. doi:10.1016/0928-0987(95)00056-9.
14. ^ Li Kam Wa TC, Freestone S, Samson RR, Johnston NR, Lee MR (July 1993). "A comparison of the effects of two putative 5-hydroxytryptamine renal prodrugs in normal man". Br J Clin Pharmacol. 36 (1): 19–23. doi:10.1111/j.1365-2125.1993.tb05886.x. PMC 1364549. PMID 7690583.
15. ^ Li Kam Wa TC, Freestone S, Samson RR, Johnston NR, Lee MR (September 1994). "The antinatriuretic action of gamma-L-glutamyl-5-hydroxy-L-tryptophan is dependent on its decarboxylation to 5-hydroxytryptamine in normal man". Br J Clin Pharmacol. 38 (3): 265–269. doi:10.1111/j.1365-2125.1994.tb04351.x. PMC 1364799. PMID 7826829.
16. ^ Aboul-Enein MN, El-Azzouny AA, Saleh OA, Maklad YA (June 2012). "On chemical structures with potent antiepileptic/anticonvulsant profile". Mini Rev Med Chem. 12 (7): 671–700. doi:10.2174/138955712800626665. PMID 22512548.
17. ^ Goldberg JS (August 2010). "Selected Gamma Aminobutyric Acid (GABA) Esters may Provide Analgesia for Some Central Pain Conditions". Perspect Medicin Chem. 4: 23–31. doi:10.4137/pmc.s5490. PMC 2918363. PMID 20703328.
18. ^ Santillo MF, Sprando RL (April 2023). "Picamilon, a γ-aminobutyric acid (GABA) analogue and marketed nootropic, is inactive against 50 biological targets". Basic Clin Pharmacol Toxicol. 132 (4): 355–358. doi:10.1111/bcpt.13836. PMID 36668678.
19. ^ Bianchi M, Quadro G, Mourier G, Galzigna L (1983). "Pharmacokinetics and in vitro effects of a 4-aminobutyric acid derivative with anticonvulsant action". Pharmacology. 27 (4): 237–240. doi:10.1159/000137876. PMID 6634934.
20. ^ a b Storer, R. James; Ferrante, Antonio (10 October 1997). "Radiochemical Assay of Diamine Oxidase". Polyamine Protocols. Methods in Molecular Biology. Vol. 79\. New Jersey: Humana Press. pp. 91–96. doi:10.1385/0-89603-448-8:91. ISBN 978-0-89603-448-8. PMID 9463822. "In biological mixtures γ-aminobutyraldehyde may be alternatively oxidized by aldehyde dehydrogenases (EC 1.2.1.3) to γ-aminobutyric acid (GABA) (11—13). The formation of 4-amino-1-butanol is also possible through reduction by aldehyde dehydrogenase and/or alcohol dehydrogenase (13,14), thus preventing cyclization. Other fates of putrescine in biological mixtures include the acetylation to acetylputrescine by an N-acetyltransferase and then oxidation by monoamine oxidase (EC 1.4.3.4) (11,17). [...] Fig 1 Fates of putrescine in biological mixtures"
21. ^ a b Felmlee MA, Morse BL, Morris ME (January 2021). "γ-Hydroxybutyric Acid: Pharmacokinetics, Pharmacodynamics, and Toxicology". AAPS J. 23 (1): 22. doi:10.1208/s12248-020-00543-z. PMC 8098080. PMID 33417072.
22. ^ Rashmi, Deo; Zanan, Rahul; John, Sheeba; Khandagale, Kiran; Nadaf, Altafhusain (2018). "γ-Aminobutyric Acid (GABA): Biosynthesis, Role, Commercial Production, and Applications". Studies in Natural Products Chemistry. Vol. 57\. Elsevier. pp. 413–452. doi:10.1016/b978-0-444-64057-4.00013-2. ISBN 978-0-444-64057-4. "Alternate pathways of GABA synthesis from putrescine and other polyamines have also been reported [207–211]. Here, γ-aminobutyraldehyde, an intermediate from polyamine degradation reaction via combined activities of diamine oxidase (DAO, E.C. 1.4.3.6) and 4-aminobutyraldehyde dehydrogenase (ABALDH), leads to the synthesis of GABA [205,212,213]. In response to abiotic stresses, GABA is also reported to be synthesized from proline via D1-pyrroline intermediate formation [47,205,214] and also by a nonenzymatic reaction [214]. However, GABA synthesis from polyamine pathways is minor in the brain, [215] although they play a significant role in the developing brain [216] and retina [217]. But GABA can be formed from putrescine in the mammalian brain [218]."
23. ^ Benedetti MS, Dostert P (1994). "Contribution of amine oxidases to the metabolism of xenobiotics". Drug Metab Rev. 26 (3): 507–535. doi:10.3109/03602539408998316. PMID 7924902. "MAO also catalyses the deamination of a natural brain constituent, monoacetyl-putrescine, producing y-acetylaminobutyraldehyde, which in turn participates in the formation of brain GABA [13]."
24. ^ Tay E, Lo WK, Murnion B (2022). "Current Insights on the Impact of Gamma-Hydroxybutyrate (GHB) Abuse". Subst Abuse Rehabil. 13: 13–23. doi:10.2147/SAR.S315720. PMC 8843350. PMID 35173515.
25. ^ Parnetti L, Mignini F, Tomassoni D, Traini E, Amenta F (June 2007). "Cholinergic precursors in the treatment of cognitive impairment of vascular origin: ineffective approaches or need for re-evaluation?". J Neurol Sci. 257 (1–2): 264–269. doi:10.1016/j.jns.2007.01.043. PMID 17331541.

* v
* t
* e

Neurotransmitters

Amino acid-derived|

| Major excitatory /
inhibitory systems|

| Glutamate system|

* Agmatine
* Aspartic acid (aspartate)
* Glutamic acid (glutamate)
* Glutathione
* Glycine
* GSNO
* GSSG
* Kynurenic acid
* NAA
* NAAG
* Proline
* Serine

|

GABA system|

* GABA
* GABOB
* GHB

Glycine system|

* α-Alanine
* β-Alanine
* Glycine
* Hypotaurine
* Proline
* Sarcosine
* Serine
* Taurine

GHB system|

* GHB
* T-HCA (GHC)

Biogenic amines|

| Monoamines|

* 6-OHM
* Dopamine
* Epinephrine (adrenaline)
* NAS (normelatonin)
* Norepinephrine (noradrenaline)
* Serotonin (5-HT)

|

Trace amines|

* 3-Iodothyronamine
* N-Methylphenethylamine
* N-Methyltryptamine
* m-Octopamine
* p-Octopamine
* Phenylethanolamine
* Phenethylamine
* Synephrine
* Tryptamine
* m-Tyramine
* p-Tyramine

Others|

* Histamine

Neuropeptides|

* See here instead.

Lipid-derived|

| Endocannabinoids|

* 2-AG
* 2-AGE (noladin ether)
* 2-ALPI
* 2-OG
* AA-5-HT
* Anandamide (AEA)
* DEA
* LPI
* NADA
* NAGly
* OEA
* Oleamide
* PEA
* RVD-Hpα
* SEA
* Virodhamine (O-AEA)

|

Neurosteroids|

* See here instead.

Nucleobase-derived|

| Nucleosides|

| Adenosine system|

* ADP
* AMP
* ATP

|

Vitamin-derived|

|

Miscellaneous|

| Cholinergic system|

* Acetylcholine

|

Gasotransmitters|

* Carbon monoxide (CO)
* Hydrogen sulfide (H2S)
* Nitric oxide (NO)

|

Candidates|

* Acetaldehyde
* Ammonia (NH3)
* Carbonyl sulfide (COS)
* Nitrous oxide (N2O)
* Sulfur dioxide (SO2)

|

* v
* t
* e

Neurotransmitter metabolic intermediates

Catecholamines|

| Anabolism|

* Phenylalanine → Tyrosine → DOPA (levodopa) → Dopamine → Norepinephrine → Epinephrine

|

Catabolism|

| Dopamine|

* 3,4-Dihydroxyphenylacetaldehyde (DOPAL)
* 3,4-Dihydroxyphenylacetic acid (DOPAC)
* Homovanillyl alcohol
* Hydroxytyrosol (3,4-dihydroxyphenylethanol; DOPET)
* 3-Methoxytyramine (3-MT)
* Homovanillic acid (HVA)

|

Norepinephrine|

* 3,4-Dihydroxyphenylglycolaldehyde (DOPEGAL, DHMAL)
* 3,4-Dihydroxymandelic acid (DHMA)
* Normetanephrine
* 3-Methoxy-4-hydroxymandelaldehyde (MHMAL)
* Vanillylmandelic acid (VMA)
* 3,4-Dihydroxyphenylethylene glycol (DOPEG, DHPG)
* 3-Methoxy-4-hydroxyphenylglycol (MHPG, MOPEG)

Epinephrine|

* 3,4-Dihydroxyphenylglycolaldehyde (DOPEGAL, DHMAL)
* Metanephrine
* 3-Methoxy-4-hydroxymandelaldehyde (MHMAL)

Tryptophan→Serotonin|

| Anabolism|

* Tryptophan
* 5-Hydroxytryptophan (5-HTP)

|

Catabolism|

* 5-Hydroxyindoleacetaldehyde (5-HIAL)
* 5-Hydroxyindoleacetic acid (5-HIAA)
* 5-Hydroxytryptophol (5-HTOL)

Serotonin→Melatonin|

* N-Acetylserotonin (NAS; normelatonin)
* 5-Methoxytryptamine (5-MT)
* 5-Methoxyindoleacetaldehyde (5-MIAL)

Trace amines|

* 3-Methoxy-4-hydroxyphenylacetaldehyde (HMPAL)
* 4-Hydroxyphenylacetaldehyde (HPAL)
* Indoleacetaldehyde (IAL)
* Phenacetaldehyde (PAL)

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