Neurotransmitter prodrug explained

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] 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. Besides their use in medicine, neurotransmitter prodrugs have also been used as recreational drugs in some cases.[2]

Monoamine prodrugs

See main article: Monoamine precursor.

Monoamine neurotransmitter prodrugs include the catecholamine precursors and prodrugs L-phenylalanine, L-tyrosine, L-DOPA (levodopa), L-DOPS (droxidopa), and dipivefrine (O,O'-dipivalylepinephrine),[3] as well as the serotonin and melatonin precursors and prodrugs L-tryptophan and L-5-hydroxytryptophan (5-HTP; oxitriptan).[4] [5] [6] 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.[7] [8] [9] [10] [11] Dopamantine (N-adamantanoyl dopamine) is another possible attempt at a dopamine prodrug.[12] [13] Other serotonin prodrugs have been developed as well, such as the renally-selective L-glutamyl-5-hydroxy-L-tryptophan (glu-5-HTP).[14] [15] [16]

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).[17] [18] [19] [20] [21] 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).[22] [23] [24] [25] 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.[26] [27] [28] [29] [30] 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.[36] [37] Picamilon has been claimed to be a prodrug of GABA, but has not actually been demonstrated to be converted into GABA.[38] [39] Pivagabine was once thought to be a prodrug of GABA, but this proved not to be the case.[40]

4-Amino-1-butanol is known to be converted into GABA through the actions of aldehyde reductase (ALR) and aldehyde dehydrogenase (ALDH).[41] 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). 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.[44] These include 1,4-butanediol (1,4-BD) and γ-butyrolactone (GBL), as well as the metabolic intermediate γ-hydroxybutyraldehyde (GHBAL).[45] [46]

Acetylcholine prodrugs

Acetylcholine precursors and prodrugs like choline, phosphatidylcholine (lecithin), citicoline (CDP-choline), and choline alphoscerate (α-GPC) are known and have been researched.[47]

References

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Notes and References

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  2. Trombley TA, Capstick RA, Lindsley CW . DARK Classics in Chemical Neuroscience: Gamma-Hydroxybutyrate (GHB) . ACS Chem Neurosci . 11 . 23 . 3850–3859 . December 2020 . 31287661 . 10.1021/acschemneuro.9b00336 .
  3. Huttunen KM, Raunio H, Rautio J . Prodrugs--from serendipity to rational design . Pharmacol Rev . 63 . 3 . 750–771 . September 2011 . 21737530 . 10.1124/pr.110.003459 .
  4. Maffei ME . 5-Hydroxytryptophan (5-HTP): Natural Occurrence, Analysis, Biosynthesis, Biotechnology, Physiology and Toxicology . Int J Mol Sci . 22 . 1 . December 2020 . 181 . 33375373 . 7796270 . 10.3390/ijms22010181 . free .
  5. Book: Dörwald, F.Z. . Lead Optimization for Medicinal Chemists: Pharmacokinetic Properties of Functional Groups and Organic Compounds . Wiley . 2012 . 978-3-527-33226-7 . 9 September 2024 . 159.
  6. Turner EH, Loftis JM, Blackwell AD . Serotonin a la carte: supplementation with the serotonin precursor 5-hydroxytryptophan . Pharmacol Ther . 109 . 3 . 325–338 . March 2006 . 16023217 . 10.1016/j.pharmthera.2005.06.004 .
  7. Gupta HV, Lyons KE, Pahwa R . Old Drugs, New Delivery Systems in Parkinson's Disease . Drugs Aging . 36 . 9 . 807–821 . September 2019 . 31161581 . 10.1007/s40266-019-00682-9 .
  8. Lees A, Tolosa E, Stocchi F, Ferreira JJ, Rascol O, Antonini A, Poewe W . 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 . January 2023 . 36729395 . 10.1080/14737175.2023.2176220 . 10451/56313 . free .
  9. Cacciatore I, Ciulla M, Marinelli L, Eusepi P, Di Stefano A . Advances in prodrug design for Parkinson's disease . Expert Opin Drug Discov . 13 . 4 . 295–305 . April 2018 . 29361853. 10.1080/17460441.2018.1429400 .
  10. Haddad F, Sawalha M, Khawaja Y, Najjar A, Karaman R . Dopamine and Levodopa Prodrugs for the Treatment of Parkinson's Disease . Molecules . 23 . 1 . December 2017 . 40 . 29295587 . 5943940 . 10.3390/molecules23010040 . free .
  11. Dhaneshwar SS, Sharma M, Patel V, Desai U, Bhojak J . Prodrug strategies for antihypertensives . Curr Top Med Chem . 11 . 18 . 2299–317 . 2011 . 21671866 . 10.2174/156802611797183285 .
  12. Lamoureux G, Artavia G . Use of the adamantane structure in medicinal chemistry . Current Medicinal Chemistry . 17 . 26 . 2967–2978 . 2010 . 20858176 . 10.2174/092986710792065027 . 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. .
  13. Book: Vernier VG, du Pont EI . Annual Reports in Medicinal Chemistry . Chapter 3. Antiparkinsonism Drugs . Elsevier . 9 . 1974 . 978-0-12-040509-1 . 10.1016/s0065-7743(08)61424-4 . 19–26 . 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..
  14. Thorré . Katrien . Sarre . S. . Twahirwa . E. . Meeusen . R. . Ebinger . G. . Haemers . A. . Michotte . Y. . 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 . 1996 . 10.1016/0928-0987(95)00056-9 . 247–256.
  15. Li Kam Wa TC, Freestone S, Samson RR, Johnston NR, Lee MR . A comparison of the effects of two putative 5-hydroxytryptamine renal prodrugs in normal man . Br J Clin Pharmacol . 36 . 1 . 19–23 . July 1993 . 7690583 . 1364549 . 10.1111/j.1365-2125.1993.tb05886.x .
  16. Li Kam Wa TC, Freestone S, Samson RR, Johnston NR, Lee MR . 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 . September 1994 . 7826829 . 1364799 . 10.1111/j.1365-2125.1994.tb04351.x .
  17. Book: Kozlenkov . Alexey . González-Maeso . Javier . The Neuroscience of Hallucinations . Animal Models and Hallucinogenic Drugs . Springer New York . New York, NY . 2013 . 978-1-4614-4120-5 . 10.1007/978-1-4614-4121-2_14 . 253–277.
  18. Halberstadt AL, Geyer MA . Effect of Hallucinogens on Unconditioned Behavior . Curr Top Behav Neurosci . Current Topics in Behavioral Neurosciences . 36 . 159–199 . 2018 . 28224459 . 5787039 . 10.1007/7854_2016_466 . 978-3-662-55878-2 .
  19. Schmid CL, Bohn LM . Serotonin, but not N-methyltryptamines, activates the serotonin 2A receptor via a β-arrestin2/Src/Akt signaling complex in vivo . J Neurosci . 30 . 40 . 13513–24 . October 2010 . 20926677 . 3001293 . 10.1523/JNEUROSCI.1665-10.2010 .
  20. Sapienza . Jacopo . The Key Role of Intracellular 5-HT2A Receptors: A Turning Point in Psychedelic Research? . Psychoactives . 2 . 4 . 13 October 2023 . 2813-1851 . 10.3390/psychoactives2040018 . free . 287–293.
  21. Vargas MV, Dunlap LE, Dong C, Carter SJ, Tombari RJ, Jami SA, Cameron LP, Patel SD, Hennessey JJ, Saeger HN, McCorvy JD, Gray JA, Tian L, Olson DE . Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors . Science . 379 . 6633 . 700–706 . February 2023 . 36795823 . 10108900 . 10.1126/science.adf0435 .
  22. Carbonaro TM, Gatch MB . Neuropharmacology of N,N-dimethyltryptamine . Brain Res Bull . 126 . Pt 1 . 74–88 . September 2016 . 27126737 . 5048497 . 10.1016/j.brainresbull.2016.04.016 . Endogenous DMT is synthesized from the essential amino acid tryptophan, which is decarboxylated to tryptamine. Tryptamine is then transmethylated by the enzyme indolethylamine-N-methyltransferase (INMT) (using S-adenosyl methionine as a substrate), which catalyzes the addition of methyl groups resulting in the production of N-methyltryptamine (NMT) and DMT. NMT can also act as a substrate for INMT-dependent DMT biosynthesis (Barker et al., 1981)..
  23. Barker SA . N, N-Dimethyltryptamine (DMT), an Endogenous Hallucinogen: Past, Present, and Future Research to Determine Its Role and Function . Front Neurosci . 12 . 536 . 2018 . 30127713 . 6088236 . 10.3389/fnins.2018.00536 . free . After the discovery of an indole-N-methyl transferase (INMT; Axelrod, 1961) in rat brain, researchers were soon examining whether the conversion of tryptophan (2, Figure 2) to tryptamine (TA; 3, Figure 2) could be converted to DMT in the brain and other tissues from several mammalian species. Numerous studies subsequently demonstrated the biosynthesis of DMT in mammalian tissue preparations in vitro and in vivo (Saavedra and Axelrod, 1972; Saavedra et al., 1973). In 1972, Juan Saavedra and Julius Axelrod reported that intracisternally administered TA was converted to N-methyltryptamine (NMT; 4, Figure 2) and DMT in the rat, the first demonstration of DMT’s formation by brain tissue in vivo..
  24. Cameron LP, Olson DE . Dark Classics in Chemical Neuroscience: N, N-Dimethyltryptamine (DMT) . ACS Chem Neurosci . 9 . 10 . 2344–2357 . October 2018 . 30036036 . 10.1021/acschemneuro.8b00101 . Like serotonin and melatonin, DMT is a product of tryptophan metabolism.25 Following tryptophan decarboxylation, tryptamine is methylated by an N-methyltransferase (i.e., INMT) with S-adenosylmethionine serving as the methyl donor. A second enzymatic methylation produces DMT (Figure 3A).26 [...] The enzyme indolethylamine N-methyltransferase (INMT) catalyzes the methylation of a variety of biogenic amines, and is responsible for converting tryptamine into DMT in mammals.140.
  25. Colosimo . Frankie A. . Borsellino . Philip . Krider . Reese I. . Marquez . Raul E. . Vida . Thomas A. . The Clinical Potential of Dimethyltryptamine: Breakthroughs into the Other Side of Mental Illness, Neurodegeneration, and Consciousness . Psychoactives . MDPI AG . 3 . 1 . 26 February 2024 . 2813-1851 . 10.3390/psychoactives3010007 . free . 93–122 . The metabolism of DMT within the body begins with its synthesis. Endogenous DMT is made from tryptophan after decarboxylation transforms it into tryptamine [22,25]. Tryptamine then undergoes transmethylation mediated by indolethylamine-N-methyltransferase (INMT) with S-adenosyl methionine (SAM) as a substrate, morphing into N-methyltryptamine (NMT) and eventually producing N,N-DMT [26]. Intriguingly, INMT is distributed widely across the body, predominantly in the lungs, thyroid, and adrenal glands, with a dense presence in the anterior horn of the spinal cord. Within the cerebral domain, regions such as the uncus, medulla, amygdala, frontal cortex, fronto-parietal lobe, and temporal lobe exhibit INMT activity, primarily localized in the soma [26]. INMT transcripts are found in specific brain regions, including the cerebral cortex, pineal gland, and choroid plexus, in both rats and humans. Although the rat brain is capable of synthesizing and releasing DMT at concentrations similar to established monoamine neurotransmitters like serotonin [27], the possibility that DMT is an authentic neurotransmitter is still speculative. This issue has been controversial for decades [28] and requires the demonstration of an activity-dependent release (i.e., Ca2+-stimulated) of DMT at a synaptic cleft to be fully established in the human brain..
  26. Book: Schmid . Cullen L. . Bohn . Laura M. . 5-HT2A Receptors in the Central Nervous System . βArrestins: Ligand-Directed Regulators of 5-HT2A Receptor Trafficking and Signaling Events . Springer International Publishing . Cham . 2018 . 978-3-319-70472-2 . 10.1007/978-3-319-70474-6_2 . 31–55.
  27. Jaster AM, de la Fuente Revenga M, González-Maeso J . Molecular targets of psychedelic-induced plasticity . J Neurochem . 162 . 1 . 80–88 . July 2022 . 34741320 . 9068831 . 10.1111/jnc.15536 .
  28. Schmid CL, Bohn LM . Serotonin, but not N-methyltryptamines, activates the serotonin 2A receptor via a β-arrestin2/Src/Akt signaling complex in vivo . J Neurosci . 30 . 40 . 13513–24 . October 2010 . 20926677 . 3001293 . 10.1523/JNEUROSCI.1665-10.2010 .
  29. Canal CE, Morgan D . Head-twitch response in rodents induced by the hallucinogen 2,5-dimethoxy-4-iodoamphetamine: a comprehensive history, a re-evaluation of mechanisms, and its utility as a model . Drug Test Anal . 4 . 7–8 . 556–576 . 2012 . 22517680 . 3722587 . 10.1002/dta.1333 .
  30. Book: Kozlenkov . Alexey . González-Maeso . Javier . The Neuroscience of Hallucinations . Animal Models and Hallucinogenic Drugs . Springer New York . New York, NY . 2013 . 978-1-4614-4120-5 . 10.1007/978-1-4614-4121-2_14 . 253–277.
  31. Glennon RA, Rosecrans JA . Indolealkylamine and phenalkylamine hallucinogens: a brief overview . Neurosci Biobehav Rev . 6 . 4 . 489–497 . 1982 . 6757811 . 10.1016/0149-7634(82)90030-6 .
  32. Book: Nichols DE, Glennon RA . 1984 . Medicinal Chemistry and Structure-Activity Relationships of Hallucinogens . Hallucinogens: Neurochemical, Behavioral, and Clinical Perspectives . 95–142 . https://www.thevespiary.org/rhodium/Rhodium/hive/hiveboard/picproxie_docs/000499541-Jacobs-Nichols-Glennon.pdf .
  33. Glennon RA, Rosecrans JA . Speculations on the mechanism of action of hallucinogenic indolealkylamines . Neurosci Biobehav Rev . 5 . 2 . 197–207 . 1981 . 7022271 . 10.1016/0149-7634(81)90002-6 .
  34. Sourkes TL . 1991 . Alpha-methyltryptophan as a therapeutic agent . Prog Neuropsychopharmacol Biol Psychiatry . 15 . 6 . 935–938 . 10.1016/0278-5846(91)90020-2 . 1763198.
  35. Book: Supuran, C.T. . Angeli . A. . Tanini . D. . Advances in Prodrugs: Design and Therapeutic Applications . Elsevier . 2024 . 978-0-443-15634-2 . 13 November 2024 . 296.
  36. Jana S, Mandlekar S, Marathe P . Prodrug design to improve pharmacokinetic and drug delivery properties: challenges to the discovery scientists . Curr Med Chem . 17 . 32 . 3874–3908 . 2010 . 20858214 . 10.2174/092986710793205426 .
  37. Aboul-Enein MN, El-Azzouny AA, Saleh OA, Maklad YA . On chemical structures with potent antiepileptic/anticonvulsant profile . Mini Rev Med Chem . 12 . 7 . 671–700 . June 2012 . 22512548 . 10.2174/138955712800626665 .
  38. Goldberg JS . Selected Gamma Aminobutyric Acid (GABA) Esters may Provide Analgesia for Some Central Pain Conditions . Perspect Medicin Chem . 4 . 23–31 . August 2010 . 20703328 . 2918363 . 10.4137/pmc.s5490 .
  39. Santillo MF, Sprando RL . Picamilon, a γ-aminobutyric acid (GABA) analogue and marketed nootropic, is inactive against 50 biological targets . Basic Clin Pharmacol Toxicol . 132 . 4 . 355–358 . April 2023 . 36668678 . 10.1111/bcpt.13836 .
  40. Bianchi M, Quadro G, Mourier G, Galzigna L . Pharmacokinetics and in vitro effects of a 4-aminobutyric acid derivative with anticonvulsant action . Pharmacology . 27 . 4 . 237–240 . 1983 . 6634934 . 10.1159/000137876.
  41. Book: Storer . R. James . Ferrante . Antonio . Polyamine Protocols . Radiochemical Assay of Diamine Oxidase . Methods in Molecular Biology . Humana Press . New Jersey . 79 . 10 October 1997 . 978-0-89603-448-8 . 10.1385/0-89603-448-8:91 . 91–96 . 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.
  42. Book: Rashmi . Deo . Zanan . Rahul . John . Sheeba . Khandagale . Kiran . Nadaf . Altafhusain . Studies in Natural Products Chemistry . γ-Aminobutyric Acid (GABA): Biosynthesis, Role, Commercial Production, and Applications . Elsevier . 57 . 2018 . 978-0-444-64057-4 . 10.1016/b978-0-444-64057-4.00013-2 . 413–452 . 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]..
  43. Benedetti MS, Dostert P . Contribution of amine oxidases to the metabolism of xenobiotics . Drug Metab Rev . 26 . 3 . 507–535 . 1994 . 7924902 . 10.3109/03602539408998316 . 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]..
  44. Ponce . Julio de Carvalho . The use of prodrugs as drugs of abuse . WIREs Forensic Science . 6 . 3 . 2024 . 2573-9468 . 10.1002/wfs2.1514 . free .
  45. Felmlee MA, Morse BL, Morris ME . γ-Hydroxybutyric Acid: Pharmacokinetics, Pharmacodynamics, and Toxicology . AAPS J . 23 . 1 . 22 . January 2021 . 33417072 . 8098080 . 10.1208/s12248-020-00543-z .
  46. Tay E, Lo WK, Murnion B . Current Insights on the Impact of Gamma-Hydroxybutyrate (GHB) Abuse . Subst Abuse Rehabil . 13 . 13–23 . 2022 . 35173515 . 8843350 . 10.2147/SAR.S315720 . free .
  47. Parnetti L, Mignini F, Tomassoni D, Traini E, Amenta F . 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 . June 2007 . 17331541 . 10.1016/j.jns.2007.01.043 .

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