Neurotransmitter prodrug

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Levodopa (L-DOPA), a prodrug of dopamine which is used to treat Parkinson's disease and certain other conditions. 3,4-Dihydroxy-L-phenylalanin (Levodopa).svg
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 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]

Contents

Monoamine prodrugs

Monoamine neurotransmitter prodrugs include the catecholamine precursors and prodrugs L-phenylalanine, L-tyrosine, L-DOPA (levodopa), L-DOPS (droxidopa), and dipivefrine (O,O'-dipivalylepinephrine), [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, and O,O'-dipivaloyldopamine, have also been developed. [9] [10] [11] [12] Dopamantine (N-adamantanoyl dopamine) is another possible attempt at a dopamine prodrug. [13] [14] Other serotonin prodrugs have been developed as well, such as the renally-selective L-glutamyl-5-hydroxy-L-tryptophan (glu-5-HTP). [15] [16] [17]

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). [18] [19] [20] [21] [22] 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). [19] [23] [24] [25] [26] 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. [19] [27] [28] [20] [29] [18] O-Acetylbufotenine and O-pivalylbufotenine are thought to be centrally active prodrugs of the peripherally selective bufotenin. [30] [31] [32]

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. [33]

GABA prodrugs

γ-Aminobutyric acid (GABA) prodrugs include progabide and tolgabide. [2] [34] Picamilon has been claimed to be a prodrug of GABA, but has not actually been demonstrated to be converted into GABA. [35] [36] Pivagabine was once thought to be a prodrug of GABA, but this proved not to be the case. [37]

4-Amino-1-butanol is known to be converted into GABA through the actions of aldehyde reductase (ALR) and aldehyde dehydrogenase (ALDH). [38] 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). [38] [39] The metabolic intermediate γ-aminobutyraldehyde (GABAL) is also converted into GABA. [40] [41]

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] [39] [42]

Acetylcholine prodrugs

Acetylcholine precursors and prodrugs like choline, phosphatidylcholine (lecithin), citicoline (CDP-choline), and choline alphoscerate (α-GPC) are known and have been researched. [43]

Related Research Articles

<i>N</i>,<i>N</i>-Dimethyltryptamine Chemical compound

N,N-Dimethyltryptamine is a substituted tryptamine that occurs in many plants and animals, including humans, and which is both a derivative and a structural analog of tryptamine. DMT is used as a psychedelic drug and prepared by various cultures for ritual purposes as an entheogen.

<span class="mw-page-title-main">Monoamine oxidase</span> Family of enzymes

Monoamine oxidases (MAO) are a family of enzymes that catalyze the oxidation of monoamines, employing oxygen to clip off their amine group. They are found bound to the outer membrane of mitochondria in most cell types of the body. The first such enzyme was discovered in 1928 by Mary Bernheim in the liver and was named tyramine oxidase. The MAOs belong to the protein family of flavin-containing amine oxidoreductases.

<span class="mw-page-title-main">Tryptophan</span> Chemical compound

Tryptophan (symbol Trp or W) is an α-amino acid that is used in the biosynthesis of proteins. Tryptophan contains an α-amino group, an α-carboxylic acid group, and a side chain indole, making it a polar molecule with a non-polar aromatic beta carbon substituent. Tryptophan is also a precursor to the neurotransmitter serotonin, the hormone melatonin, and vitamin B3 (niacin). It is encoded by the codon UGG.

α-Methyltryptamine Chemical compound

α-Methyltryptamine is a psychedelic, stimulant, and entactogen drug of the tryptamine family. It was originally developed as an antidepressant at Upjohn in the 1960s, and was used briefly as an antidepressant in the Soviet Union under the brand name Indopan or Indopane before being discontinued.

<span class="mw-page-title-main">GABA</span> Main inhibitory neurotransmitter in the mammalian brain

GABA is the chief inhibitory neurotransmitter in the developmentally mature mammalian central nervous system. Its principal role is reducing neuronal excitability throughout the nervous system.

<span class="mw-page-title-main">Tryptamine</span> Metabolite of the amino acid tryptophan

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. The structure of tryptamine is a shared feature of certain aminergic neuromodulators including melatonin, serotonin, bufotenin and psychedelic derivatives such as dimethyltryptamine (DMT), psilocybin, psilocin and others.

A biogenic amine is a biogenic substance with one or more amine groups. They are basic nitrogenous compounds formed mainly by decarboxylation of amino acids or by amination and transamination of aldehydes and ketones. Biogenic amines are organic bases with low molecular weight and are synthesized by microbial, vegetable and animal metabolisms. In food and beverages they are formed by the enzymes of raw material or are generated by microbial decarboxylation of amino acids.

<span class="mw-page-title-main">5-Hydroxytryptophan</span> Chemical compound

5-Hydroxytryptophan (5-HTP), used medically as oxitriptan, is a naturally occurring amino acid and chemical precursor as well as a metabolic intermediate in the biosynthesis of the neurotransmitter serotonin.

<i>N</i>-Methyltryptamine Chemical compound

N-Methyltryptamine (NMT) is a member of the substituted tryptamine chemical class and a natural product which is biosynthesized in the human body from tryptamine by certain N-methyltransferase enzymes, such as indolethylamine N-methyltransferase. It is a known component in human urine. NMT is an alkaloid derived from L-tryptophan that has been found in the bark, shoots and leaves of several plant genera, including Virola, Acacia, Mimosa, and Desmanthus—often together with the related compounds N,N-dimethyltryptamine (DMT) and 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT).

γ-Amino-β-hydroxybutyric acid Anticonvulsant drug

γ-Amino-β-hydroxybutyric acid (GABOB), also known as β-hydroxy-γ-aminobutyric acid (β-hydroxy-GABA), sold under the brand name Gamibetal among others, is an anticonvulsant which is used for the treatment of epilepsy in Europe, Japan, and Mexico. It is a GABA analogue, or an analogue of the neurotransmitter γ-aminobutyric acid (GABA), and has been found to be an endogenous metabolite of GABA.

<span class="mw-page-title-main">GABA reuptake inhibitor</span> Drug class

A GABA reuptake inhibitor (GRI) is a type of drug which acts as a reuptake inhibitor for the neurotransmitter gamma-Aminobutyric acid (GABA) by blocking the action of the gamma-Aminobutyric acid transporters (GATs). This in turn leads to increased extracellular concentrations of GABA and therefore an increase in GABAergic neurotransmission. Gamma-aminobutyric acid (GABA) is an amino acid that functions as the predominant inhibitory neurotransmitter within the central nervous system, playing a crucial role in modulating neuronal activity in both the brain and spinal cord. While GABA predominantly exerts inhibitory actions in the adult brain, it has an excitatory role during developmental stages. When the neuron receives the action potential, GABA is released from the pre-synaptic cell to the synaptic cleft. After the action potential transmission, GABA is detected on the dendritic side, where specific receptors collectively contribute to the inhibitory outcome by facilitating GABA transmitter uptake. Facilitated by specific enzymes, GABA binds to post-synaptic receptors, with GABAergic neurons playing a key role in system regulation. The inhibitory effects of GABA diminish when presynaptic neurons reabsorb it from the synaptic cleft for recycling by GABA transporters (GATs). The reuptake mechanism is crucial for maintaining neurotransmitter levels and synaptic functioning. Gamma-aminobutyric acid Reuptake Inhibitors (GRIs) hinder the functioning of GATs, preventing GABA reabsorption in the pre-synaptic cell. This results in increased GABA levels in the extracellular environment, leading to elevated GABA-mediated synaptic activity in the brain.

α-Methylserotonin Chemical compound

α-Methylserotonin (αMS), also known as α-methyl-5-hydroxytryptamine (α-methyl-5-HT) or 5-hydroxy-α-methyltryptamine (5-HO-αMT), is a tryptamine derivative closely related to the neurotransmitter serotonin (5-HT). It acts as a non-selective serotonin receptor agonist and has been used extensively in scientific research to study the function of the serotonin system.

<span class="mw-page-title-main">Substituted tryptamine</span> Class of indoles

Substituted tryptamines, or serotonin analogues, are organic compounds which may be thought of as being derived from tryptamine itself. The molecular structures of all tryptamines contain an indole ring, joined to an amino (NH2) group via an ethyl (−CH2–CH2−) sidechain. In substituted tryptamines, the indole ring, sidechain, and/or amino group are modified by substituting another group for one of the hydrogen (H) atoms.

<span class="mw-page-title-main">Monoamine precursor</span>

Monoamine precursors are precursors of monoamines and monoamine neurotransmitters in the body. The amino acids L-tryptophan and L-5-hydroxytryptophan are precursors of serotonin and melatonin, while the amino acids L-phenylalanine, L-tyrosine, and L-DOPA (levodopa) are precursors of dopamine, epinephrine (adrenaline), and norepinephrine (noradrenaline).

<i>O</i>-Acetylbufotenine Psychedelic tryptamine

O-Acetylbufotenine, or bufotenine O-acetate, also known as 5-acetoxy-N,N-dimethyltryptamine (5-AcO-DMT) or O-acetyl-N,N-dimethylserotonin, is a synthetic tryptamine derivative and putative serotonergic psychedelic. It is the O-acetylated analogue of the naturally occurring peripherally selective serotonergic tryptamine bufotenine and is thought to act as a centrally penetrant prodrug of bufotenine.

γ-Aminobutyraldehyde, also known as 4-aminobutanal, 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 oxidase (DAO) and aminobutyraldehyde dehydrogenase (ABALDH). Putrescine is converted into ABAL via monoamine oxidase B (MAO-B). However, biosynthesis of GABA from polyamines like putrescine is a minor metabolic pathway in the brain.

4-Amino-1-butanol, or 4-aminobutanol, also known as 4-hydroxybutylamine, is an alkanolamine and an analogue and precursor of the neurotransmitter γ-aminobutyric acid (GABA).

α-Methyltryptophan Serotonergic drug

α-Methyltryptophan is a synthetic tryptamine derivative, an artificial amino acid, and a prodrug of α-methylserotonin (αMS). It is the α-methylated derivative of tryptophan, while αMS is the α-methylated analogue of serotonin. αMTP has been suggested for potential therapeutic use in the treatment of conditions thought by some authors to be related to serotonin deficiency, such as depression. In labeled forms, αMTP is also used as a radiotracer in positron emission tomography (PET) imaging to assess serotonin synthesis and certain other processes.

α-Methyl-5-hydroxytryptophan Monoaminergic agent

α-Methyl-5-hydroxytryptophan (α-Me-5-HTP) is a synthetic tryptamine derivative, an artificial amino acid, and a prodrug of α-methylserotonin. It is the α-methylated derivative of 5-hydroxytryptophan (5-HTP), while αMS is the α-methylated analogue of serotonin. Along with α-methyltryptophan (α-MTP), α-Me-5-HTP has been suggested for potential therapeutic use in the treatment of conditions thought by some authors to be related to serotonin deficiency, such as depression.

O-Pivalylbufotenine, or bufotenine O-pivalate, also known as 5-pivaloxy-N,N-dimethyltryptamine or O-pivalyl-N,N-dimethylserotonin, is a synthetic tryptamine derivative and putative serotonergic psychedelic. It is the O-pivalyl analogue of the naturally occurring but peripherally selective serotonergic tryptamine bufotenine and is thought to act as a centrally penetrant prodrug of bufotenine.

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  38. 1 2 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
  39. 1 2 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.
  40. ↑ 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].
  41. ↑ 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].
  42. ↑ 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.
  43. ↑ 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.