Dopamine and Related Drugs as Anti-Inflammatories and Antioxidants: Comparison
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Dopamine (DA), its derivatives, and dopaminergic drugs are compounds widely used in the management of diseases related to the nervous system. However, DA receptors have been identified in nonneuronal tissues, which has been related to their therapeutic potential in pathologies such as sepsis or septic shock, blood pressure, renal failure, diabetes, and obesity, among others. In addition, DA and dopaminergic drugs have shown anti-inflammatory and antioxidant properties in different kinds of cells. 

  • dopamine
  • anti-inflammatory
  • antioxidant
  • antiangiogenic
  • antinociceptive
  • nonneurological disease

1. Introduction

Dopamine (DA) is a monoamine synthesized mainly in neurons of the midbrain cores, ventral tegmental area, and substantia nigra pars compacta. The synthesis of the neurotransmitter takes place in the dopaminergic nerves [1]. Hydroxylation of the amino acid L-tyrosine is the point of regulation of the synthesis of catecholamines, including DA, in the central nervous system (CNS), and consequently, the tyrosine hydroxylase (TH) enzyme is the limiting enzyme of the synthesis of DA, norepinephrine, and adrenaline. Through their receptors, DA has been shown to have physiological functions in the CNS, such as wakefulness, attention, memory formation and consolidation, novelty-induced memory encoding, and reward/addiction [2,3,4,5][2][3][4][5]. DA is a neuromodulator that has the ability to diffuse away from the site of its release, activating receptors that are far from the terminal; this ability is called transmission volume [2]. In this sense, DA receptors have been identified in nonneuronal tissues, which has been related to their therapeutic potential in pathologies such as sepsis or septic shock, blood pressure, renal failure, diabetes, and obesity, among others [6,7,8][6][7][8]. In addition, it has been reported that DA and dopaminergic drugs such as bromocriptine, cabergoline, pramipexole, and ropinirole have shown anti-inflammatory and antioxidant functions in different kinds of cells, reducing reactive oxygen species (ROS) accumulation, preserving glutathione (GSH) and other antioxidant enzymes, and decreasing lipid peroxidation [9,10,11,12,13,14][9][10][11][12][13][14]. Additionally, some herbal compounds have shown dopaminergic properties; for example, Hepad S1, a Korean medicinal herbal combination, is an important source of dopamine with neuroprotective properties that improve Parkinson’s symptoms; it could modulate adverse cellular events such as inflammation and oxidation in neuronal cells [15]. Curcumine has shown neuroprotective properties and is an important component of dopamine [16], and Hordenine, a natural compound of germinated barley, is an agonist of the dopamine D2 receptor [17]. These and other herbs have been mainly studied in neuronal diseases, with less research in nonneuronal diseases.

2. Dopamine Synthesis, Release, Catabolism, and Postsynaptic Action

This section describes DA and its pharmacological properties at the molecular level. The synthesis of DA (Figure 1) begins with the hydroxylation of L-tyrosine by the TH enzyme to generate L-3,4-dihydroxyphenylalanine (L-DOPA); then, aromatic L-amino acid decarboxylase (AADC or DOPA decarboxylase) allows the production of cytosolic dopamine [18,19,20][18][19][20]. The DA synthesized in the presynaptic terminal is loaded in synaptic vesicles by vesicular monoamine transporter 2 (VMAT-2); subsequently, DA is released to the synaptic cleft. Next, the Na+-dependent dopamine transporter (DAT), localized in neurons and glial cells, reuptakes the neurotransmitter [18]. DA is recycled into synaptic vesicles or degraded by specialized enzymes [21], where its catabolism takes place. In presynaptic terminal and glial cells, the monoamine oxidase (MAO) enzyme, localized in mitochondria, breaks down DA through oxidative deamination, producing 3,4-dihydroxyphenylacetaldehyde (DOPAL); in turn, aldehyde dehydrogenase (ALDH) converts DOPAL to carboxylic acid 3,4-dihydroxyphenylacetic acid (DOPAC) by oxidation, or alcohol dehydrogenase (ADH) reduces DOPAL to 3,4-dihydroxyphenylethanol (DOPET) [20,22][20][22]. The catechol O-methyl-transferase (COMT) enzyme, localized in the synaptic cleft, catalyzes the methylation of dopamine to 3-methoxytyramine (3-MT), which is a MAO substrate that forms 3-methoxy-4-hydroxyphenylacetaldehyde (HMPAL). Finally, the ALDH enzyme catalyzes HMPAL to generate homovanillic acid (HVA), which is the main end-product of DA degradation [20,22,23][20][22][23]. At the post-synapse, DA binds to D1-like and D2-like receptors, which are G-protein-coupled channels [24]. The D1-like receptor activates the Gαs/olf subunit protein that stimulates the adenylyl cyclase (AC) protein; then, it generates the cyclic adenosine monophosphate (cAMP) second messenger, which activates protein kinase A (PKA), resulting in target action and increasing protein phosphorylation. On the other hand, the D2-like receptor, by activating the Gαi/o subunit, inhibits the effector protein AC, inhibiting the cAMP second messenger and, thereby, PKA, generating a decrease in protein phosphorylation [18,24,25,26][18][24][25][26].
Figure 1. Synthesis, release, catabolism, and postsynaptic action of dopamine. Synthesis: The TH enzyme converts L-tyrosine to L-DOPA; then, the AADC enzyme allows the production of dopamine, which is loaded into synaptic vesicles by VMAT-2. Release and recycling: once released in the synaptic cleft, the DAT transporter reuptakes dopamine, which is recycled into synaptic vesicles. Catabolism: Dopamine is degraded by specialized enzymes; the MAO enzyme breaks down dopamine to DOPAC and DOPET. In the synaptic cleft, the COMT enzyme catalyzes dopamine to HVA, which is the main end-product of dopamine degradation. At the post-synapse, dopamine binds with D1-like and D2-like receptors. The D1-like receptor activates the Gαs/olf subunit, which stimulates adenylyl cyclase protein, increasing protein phosphorylation. D2-like receptor, by activating the Gαi/o subunit, inhibits the protein adenylyl cyclase, generating a decrease in protein phosphorylation. TH: tyrosine hydroxylase, L-DOPA: L-3,4-dihydroxyphenylalanine, AADC: L-amino acid decarboxylase, VMAT-2: vesicular monoamine transporter 2, DAT: dopamine transporter, MAO: monoamine oxidase, DOPAL: 3,4-dihydroxyphenylacetaldehyde, ALDH: aldehyde dehydrogenase, DOPAC: 3,4-dihydroxyphenylacetic acid, ADH: alcohol dehydrogenase, DOPET: 3,4-dihydroxyphenylethanol, COMT: catechol O-methyl-transferase, HMPAL: 3-methoxy-4-hydroxyphenylacetaldehyde, HVA: homovanillic acid.

3. Chemical Compounds and Drugs Related to the Dopaminergic System

There are more than 200 chemical compounds and drugs related to the dopaminergic system [27,28,29][27][28][29], and mentioning each of them is beyond the scope of this wdiscussiorkn; however, they can be grouped, according to their activity, as precursors [30,31[30][31][32][33],32,33], agonists and antagonists of receptors [34], DA reuptake inhibitors [35,36][35][36] DA releasing agents [36,37][36][37], activity enhancers [38,39,40][38][39][40], and enzyme inhibitors [41], among others. Three DA precursors are used in the clinic, L-phenylalanine, L-tyrosine, and L-DOPA; tyrosine is a nonessential amino acid that is synthesized from the essential aromatic amino acid phenylalanine, and both amino acids constitute the two initial steps in the biosynthesis of DA [31]. Levodopa (L-DOPA) is a dopamine precursor and is the most effective and commonly used drug for the treatment of Parkinson’s disease. Levodopa is prescribed in most cases with Carbidopa, which is an inhibitor of L-amino acid decarboxylase, the enzyme that metabolizes levodopa peripherally [42]. DA agonists exert their effects by acting directly on dopamine receptors and mimicking endogenous neurotransmitters. There are two subclasses, ergoline, and nonergoline agonists, with a variable affinity for different DA receptors [43,44][43][44]. DA antagonists block the effects of dopamine or its agonists by binding to DA receptors. A variety of DA antagonists are used for the treatment of psychotic disorders; however, their therapeutic effects are mostly due to long-term adjustments rather than acute blockade of DA receptors [29]. Some DA antagonists have been used to treat Tourette’s syndrome or hiccups [45,46][45][46], and they have also been used as antiemetics to treat various causes of nausea and vomiting [47]. Table 1 details the mechanisms of action and indications of DA precursors and the most representative dopaminergic agonist and antagonist drugs.
Table 1.
Mechanism of action and indications of dopamine precursors and dopaminergic agonist and antagonist drugs.
Drug Mechanism of Action Indications
Precursors
Levodopa (L-DOPA) Levodopa mimics the role of endogenous dopamine; crosses the blood–brain barrier through various pathways, and is decarboxylated to form dopamine stimulating the dopamine receptors Parkinson’s disease [29,30][29][30]
L-phenylalanine Precursor of tyrosine, dopamine, norepinephrine (noradrenaline) and epinephrine (adrenaline) Antidepressant effects

Vitiligo [31,32][31][32]
L-tyrosine Precursor of dopamine,

norepinephrine and epinephrine		 Antidepressant [31,33][31][33]
Receptor agonists
Apomorphine A nonergoline dopamine agonist with binding affinity to dopamine D2, D3, and D5 receptors Parkinson’s disease [29,42,48][29][42][48]
Bromocriptine Ergoline derivative with strong agonist activity on the D2 dopamine receptors Parkinsonian Syndrome

Amenorrhea

Galactorrhea

Acromegaly

Premenstrual syndrome

Female infertility [29,42][29][42]
Cabergoline Ergoline derivative; dopamine agonist (with a high affinity for D2 receptors) and prolactin inhibitor. Hyperprolactinemic disorders.

Parkinsonian Syndrome [29,49,50][29][49][50]
DA Agonist to the D1, D2, D3, D4, D5 dopamine receptors. Interacts on the synaptic terminals, causing neuronal excitation or inhibition at the target neuron Hemodynamic imbalances

Blood pressure

Hypotension

Poor perfusion of vital organs

Low cardiac output [29,51][29][51]
Fenoldopam Benzazepine derivative; selective dopamine D1 receptor agonist. Decreases peripheral vascular resistance in renal capillary beds Hypertension [29,52][29][52]
Lisuride Ergoline derivative, agonist to dopamine D2 receptors. It can be an antagonist to dopamine D1 receptors. Additionally, activates some serotonin receptors Parkinson’s disease [27,29][27][29]
Piribedil Nonergoline, piperazine derivative, dopamine agonist that acts on D2 and D3 receptors Parkinson’s disease [53]
Pramipexole Nonergoline, a dopamine agonist showing specificity and strong activity at dopamine D2 receptors Parkinson’s disease

Restless legs syndrome [54,55][54][55]
Quinagolide Nonergoline derivative; it selectively binds to D2 receptors on the surface of lactotroph cells, resulting in reduced adenylyl cyclase activity and inhibition of prolactin secretion from the anterior pituitary Hyperprolactinemia [27,29][27][29]
Ropinirole Nonergoline derivative, selectively binds to dopamine D2 receptors, with highest affinity at D3 receptors Parkinson’s disease

Restless legs syndrome [56,57][56][57]
Rotigotine Nonergoline derivative; a nonselective agonist of dopamine receptors with higher affinity at D3 receptors Parkinson’s disease

Restless legs syndrome [29,42][29][42]
Experimental agonists
Dihydrexidine (LS-186,899) Selective full agonist at the dopamine D1 receptors. It has some affinity for the D2 receptor Scientific research [58,59][58][59]
Pukateine Aporphine derivative; agonist at the D2 dopamine receptor and antagonist at the α1 adrenergic receptor Scientific research [60,61][60][61]
Quinpirole Selective D2 and D3 receptor agonist Scientific research [62,[6263]][63]
SKF 38393 A selective D1-like receptor agonist Scientific research [64]
Antagonists and receptor blockers
Typical antipsychotics
Chlorpromazine Phenothiazine derivative. It binds strongly to the D2 receptor, blocking its action; this blockade, in the nigrostriatal pathway, is responsible for its extrapyramidal side effects Schizophrenia, Bipolar disorder

Acute psychosis, Nausea and vomiting

Relief of apprehension before surgery

Persistent singultus (chronic hiccups) [29,46,65][29][46][65]
Fluphenazine Phenothiazine derivative. Blocks postsynaptic mesolimbic dopaminergic D2 receptors in the brain Management of psychosis in schizophrenia [29,66][29][66]
Haloperidol It is a first-generation antipsychotic and one of the most frequently used worldwide. It is not selective for the D2 receptor, but, has a strong antagonism to this dopamine receptor in mesolimbic and mesocortical pathways in the brain Schizophrenia

Tourette syndrome

Behavioral disorders in children

Hyperactivity [29,45][29][45]
Loxapine Dibenzoazepine tricyclic derivative. Antagonist with high affinity for the D2 receptor, also a serotonin 5-HT2 blocker Schizophrenia

Other psychotic disorders [27,67][27][67]
Molindone Indole derivative. Antagonizes dopamine D2 receptor sites in the reticular limbic systems in the brain, decreasing dopamine activity Schizophrenia [27,29][27][29]
Perphenazine Phenothiazine derivative. It binds to the dopamine D1 and dopamine D2 receptors inhibiting their activity. Its antiemetic effect is mainly due to blockade of D2 receptors in the chemoreceptor trigger zone and the vomiting center Schizophrenia

Other psychotic disorders

Nausea and vomiting [27,29][27][29]
Pimozide Diphenylbutylpiperidine derivative. It binds and inhibits the dopamine D2 receptor Tourette syndrome

Schizophrenia [27,42][27][42]
Thioridazine Phenothiazine derivative. It blocks postsynaptic mesolimbic dopaminergic D1 and D2 receptors Schizophrenia

Other psychotic disorders

Generalized anxiety disorder

Depressive disorders [27,68][27][68]
Thiothixene Thioxanthene derivative. Is a highly potent antagonist of the D1, D2, D3 and D4 dopamine receptors. Schizophrenia [27,29][27][29]
Atypical antipsychotics
Amisulpride Benzamide derivative. It is a selective dopamine D2 and D3 receptor antagonist Schizophrenia

Nausea and vomiting [27,29][27][29]
Clozapine Dibenzodiazepine derivative. It binds to the D4 dopamine receptors with a higher affinity than D2 receptor. Additionally, it has antagonistic effects at 5-HT2A receptors and is a partial agonist at 5-HT1A receptors Resistant schizophrenia [27,69][27][69]
Olanzapine Thienobenzodiazepine derivative. It exerts its action primarily on dopamine D1, D2, D3 and D4 and serotonin 5-HT2A, 5-HT2C, 5-HT3 and 5-HT6 receptors, blocking their action Schizophrenia,

Bipolar disorder [27,70][27][70]
Quetiapine Thiazepine derivative. Antagonizes to D2 dopamine receptors and to 5-HT2A receptors (it has strong affinity for the latter) Schizophrenia

Bipolar disorder

Major depressive disorder [27,71][27][71]
Risperidone Benzisoxazole derivative. It blocks D2, but more 5-HT2A receptors in the brain. Schizophrenia,

Bipolar mania

Autism-associated irritability [29,72][29][72]
Sulpiride Benzamide derivative. Selective antagonist at dopamine D2, D3 receptors Schizophrenia [27,29][27][29]
Ziprasidone Benzothiazolylpiperazine derivative. Binds to 5-HT2A and dopamine D2 receptors with high affinity Schizophrenia

Bipolar mania

Acute agitation in schizophrenic patients [29,73][29][73]
Antiemetics
Domperidone Benzimidazole derivative. It has strong affinity for the D2 and D3 dopamine receptors, blocking their activity Peristaltic stimulant, Dyspepsia,

Indigestion, Epigastric pain

Nausea and vomiting [27,29,74][27][29][74]
Metoclopramide Benzamide derivative. Inhibit dopamine D2 and serotonin 5-HT3 receptors Nausea and vomiting

Gastroesophageal reflux disease [29,75][29][75]
Prochlorperazine Phenothiazine derivative. It mainly blocks the D2 dopamine receptors in the mesolimbic system Schizophrenia, Schizoaffective

Other conditions with psychosis symptoms

Nausea and vomiting [29,76][29][76]
Experimental antagonists
Eticlopride Antagonizes D2 dopamine receptor Scientific research [77]
Raclopride Potent and selective antagonist on D2/D3 dopamine receptors Trials studying Parkinson’s disease [29,78][29][78]
SCH23390 Highly potent and selective of D1 dopamine receptor Scientific research of drug addiction [79]
On the other hand, DA reuptake inhibitors may be classified as DAT inhibitors and VMAT inhibitors. The former block the action of DAT, and DA reuptake inhibition occurs when extracellular DA, which does not bind to the postsynaptic neuron, is blocked from re-entering the presynaptic neuron, resulting in increased extracellular concentrations of DA and an increase in dopaminergic neurotransmission [80]. DAT inhibitors are indicated for the treatment of attention deficit hyperactivity disorder, major depressive disorder, and seasonal affective disorder and as an aid to smoking cessation; examples are methylphenidate [27,29][27][29]. On the other hand, VMAT inhibitors prevent the reuptake and storage of monoamine neurotransmitters in synaptic vesicles, making them vulnerable to metabolism by cytosolic enzymes. Inhibition of VMAT-2 results in decreased reuptake of monoamines and depletion of their reserves in nerve terminals. They are used to treat chorea due to neurodegenerative diseases or dyskinesias due to neuroleptic medications; examples are tetrabenazine, deutetrabenazine, and valbenazine [27,42,81,82,83][27][42][81][82][83]. DA-releasing agents are a type of drug that induces, through various mechanisms, the release of DA from the presynaptic neuron into the synaptic cleft, leading to an increase in extracellular concentrations of the neurotransmitter. Examples are amphetamine, lisdexamfetamine (L-lysine-d-amphetamine; vyvanse), methamphetamine, methylenedioxymethamphetamine (MDMA), and 4-methylaminorex [27,84,85,86,87][27][84][85][86][87]. Moreover, (-)1-(benzofuran-2-yl)-2-propylaminopentane, (-)BPAP, (-)-1-phenyl-2-propylaminopentane, and (-)PPAP are enhancers of dopamine activity. BPAP and PPAP act as potent stimulants of neurotransmitter release in dopaminergic neurons, leaving MAO activity largely unchanged. BPAP and PPAP controllably increase the quantity of neurotransmitters that are released when a neuron is stimulated by a neighboring neuron, and they are currently in the research phase [39,88,89][39][88][89]. DA enzyme inhibitors can be classified into DA synthesis inhibitors and DA degradation inhibitors. There are three kinds of dopamine synthesis inhibitors: (1) TH inhibitors (for example, 3-iodo-tyrosine and metyrosine), which are able to inhibit TH activity, the rate-limiting enzyme in DA biosynthesis [90]; (2) phenylalanine hydroxylase inhibitors (for example, 3,4-dihydroxystyrene), which inhibit the enzyme that converts phenylalanine to tyrosine [91]; and (3) DOPA decarboxylase inhibitors, which block the biosynthesis of L-DOPA to DA. Examples of these inhibitors are benserazide and carbidopa, commonly used in combination with levodopa. Since they can hardly cross the blood–brain barrier, they prevent the formation of dopamine in extracerebral tissues, minimizing the occurrence of extracerebral side effects [92,93][92][93]. Finally, the main DA degradation inhibitors can be classified into MAO and COMT inhibitors. The most prescribed MAO inhibitors are selegiline, isocarboxazid, phenelzine, and tranylcypromine. They have in common the ability to block oxidative deamination of DA and subsequently provoke its elevation in brain levels, enhancing dopaminergic activity [29,94][29][94]. Selegiline is close structurally to (-) methamphetamine and is a selective and irreversible inhibitor of monoamine oxidase type B (MAO-B). Selegiline is the first catecholaminergic activity-enhancing substance in clinical use that does not continually release catecholamines and is, therefore, free of amphetamine dependence [38,40][38][40]. Likewise, the most common COMT inhibitors are entacapone, opicapone, and tolcapone. They inhibit the COMT enzyme and are frequently used in the treatment of Parkinson’s disease as an adjunct to levodopa/carbidopa medication [95,96,97][95][96][97]. Many Parkinson’s disease patients treated with levodopa plus carbidopa experience motor complications over time; when COMT inhibitors are administered, plasma levodopa levels are increased and maintained, resulting in more consistent dopaminergic stimulation, leading to further reduction of the manifestations of parkinsonian syndrome [98]. In summary, dopaminergic compounds and drugs act through a variety of mechanisms of action within the process of synthesis, release, catabolism, and postsynaptic action of dopamine, as shown in Figure 2. It should be noted that these main mechanisms are often accompanied by secondary mechanisms (such as antioxidant or anti-inflammatory mechanisms, see below, which are not yet fully understood) that give a wide variety of effects and indications as potential adjuvants in most chronic and degenerative diseases.
Figure 2. Mechanism of action of chemical compounds and drugs related to the dopaminergic system. These drugs can inhibit or activate diverse proteins involved in dopamine metabolism, including precursors, enzyme inhibitors, dopamine-releasing agents, dopamine reuptake inhibitors, dopamine activity enhancers, and agonists or antagonists of D1-like and D2-like receptors. At presynapses: The precursors enable the biosynthesis of dopamine. VMAT inhibitors prevent the storage of monoamines in synaptic vesicles, resulting in the depletion of these neurotransmitters. DAT inhibitors keep dopamine in the synaptic cleft longer by inhibiting its reuptake. Dopamine-releasing agents and dopamine activity enhancers increase the release of the activity of dopamine into the synaptic cleft. Dopamine synthesis inhibitors prevent the formation of dopamine as an endpoint. Dopamine degradation inhibitors enhance dopaminergic activity by blocking dopamine catabolism. At postsynapses: The dopamine agonist (orange box) mimics endogenous dopamine function, thus activating or inhibiting adenylyl cyclase depending on whether it binds to D1-like or D2-like receptors, respectively. Dopamine antagonists (pink box) bind to but do not activate dopamine receptors, thereby blocking the actions of dopamine. L-Phe: L-phenylalanine, L-Tyr: L-tyrosine, TH: tyrosine hydroxylase, L-DOPA: L-3,4-dihydroxyphenylalanine, AADC: L-amino acid decarboxylase, VMAT2: vesicular monoamine transporter 2, DAT: dopamine transporter, MAO: monoamine oxidase, DOPAC: 3,4-dihydroxyphenylacetic acid, DOPET: 3,4-dihydroxyphenylethanol, COMT: catechol O-methyl-transferase, HVA: homovanillic acid, D1: dopamine 1 receptor, D2: dopamine 2 receptor.

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