Dopamine antagonist

A dopamine antagonist (antidopaminergic) is a type of drug

which blocks dopamine receptors by receptor antagonism.
Most antipsychotics are dopamine antagonists, and as such
they have found use in treating schizophrenia, bipolar
disorder, and stimulant psychosis.[1] Several other dopamine
antagonists are antiemetics used in the treatment of nausea
and vomiting.

Receptor Pharmacology

Dopamine Receptor Flow Chart

All dopamine receptors are G-protein coupled and are divided

into 2 classes based on which G-protein they are coupled to.[2]
The D1-like class of dopamine receptors is coupled to Gαs/olf
and stimulates adenylate cyclase production, whereas the D2-
like class is coupled to Gαi/o and thus
Dopamine
inhibits adenylate cyclase production.[2]
receptor
antagonist
D1-like receptors: D1 and D5 Dopaminergic
blockers
These receptors are always found post-
synaptically. The genes coding these Drug class

receptors lack introns, so there are no

splice variants.

D1 receptors Skeletal structor

formula of
Found mainly on neurons in the Haloperidol, a typical
nucleus accumbens[3] as well as antipsychotic
substantia nigra[2], striatum[2], Class identifiers
amygdala[2], frontal cortex[2] and Use Schizophrenia,
olfactory bulb and retina[2] bipolar
disorder,
Also found (in lower levels) in the
nausea and
hypothalamus, thalamus, cerebellum
vomiting, etc.
and hippocampus[2]
ATC code N05A
Peripherally, these receptors have
Biological Dopamine
been found in the renal artery, target receptors
mesenteric artery, and splenic artery
External links
where activation leads to
MeSH D012559
vasodilation.[4] In addition, D1
In Wikidata
 receptors have been found in the
kidney[4]

D5 receptors

Low levels of D5 receptors have been found in the

hypothalamus, prefontal cortex and cingulate cortex; as
well as memory areas such as hippocampus, dentate gyrus
and entorhinal cortex[2].
In addition, D5 receptors have been found in the kidney[4]

D2-like receptors: D2, D3 and D4

Unlike the D1-like class, these receptors are found pre and
post-synaptically. The genes that code these receptors have
introns, leading to many alternately spliced variants.

D2 receptors

D2 receptors are found in the striatum, substantia nigra,

ventral tegmental area, hypothalamus, cortex, septum,
amygdala, hippocampus, and olfactory tuburcle[2].
These receptors have also been found in the retina and
pituitary gland.[2]
Peripherally, these receptors have been found in the renal,
mesenteric, and splenic arteries as well as on the adrenal
cortex and medulla and within the kidney[4]
D3 receptors

These receptors are highly expressed on neurons in islands

of Calleja and nucleus accumbens shell and lowly
expressed in areas such as the substantia nigra pars
compacta, hippocampus, septal area, and ventral tegmental
area.[2][3]
Additional studies have found these receptors periperally in
the kidney[4]

D4 receptors

These receptors are found in amygdala, hippocamps,

hypothalamus, globus pallidus, substantia nigra pars
reticula, the thalamus, the retina and the kidney [2][4]

Implications in Disease
The dopaminergic system has been implicated in a variety of
disorders. Parkinson's disease results from loss of
dopaminergic neurons in the striatum[5]. Furthermore, most
effective antipsychotics block D2 receptors, suggesting a role
for dopamine in schizophrenia[5][6][7]. Additional studies
hypothesize dopamine dysregulation is involved in
Huntington's disease, ADHD, Tourette's syndrome, major
depression, manic depression, addiction, hypertension and
kidney dysfunction.[5][7][8] Dopamine receptor antagonists are
used for some diseases such as schizophrenia, bipolar
disorder, nausea and vomiting[5].

Melatonin suppresses dopamine activity[9] as part of

normal circadian rhythm functions, although pathological
imbalances have been implicated in Parkinson's disease[10]

Side effects
They may include one or more of the following and last
indefinitely even after cessation of the dopamine antagonist,
especially after long-term or high-dosage use:

Cardiovascular disease[11][12]

Extrapyramidal symptoms (EPS) associated with typical

antipsychotics:
Early Stages - occurs at onset of treatment or following
increased dose, patients recover when dose is
decreased[13]
Acute dystonias[13] - muscle spasms and
sustained abnormal postures and onset occurs
 within a few days; can be treated with
anticholinergics
risk factors include age, gender and family
history[13]
Akathisia[14][13] - pacing and restlessness and
onset occurs within the first few months; can be
treated with beta blockers and benzodiazepines
Parkinsonism due to effects on the nigrostriatal
pathway[14][13] - includes tremors, bradykinesia and
muscle rigidity
risk factors include age and gender[13]
Later stage - occurs after prolonged (months-years)
treatment, symptoms persist even after dose is
decreased[13]
Tardive dyskinesia [14][13] - includes involuntary and
repetitive facial movements
risk factors include age, race and gender[13]
It is hypothesized that these effects are due to chronic
blockade of the D2 receptor[14]
Hyperprolactinaemia due to blockade of the D2 receptors in
the anterior pituitary leading to increased prolactin
release[11][15]
Increased appetite including increased craving and binge
eating that lead to weight gain[16][11][17]
 Increased risk for insulin resistance[16]
Sexual dysfunction[11][12]
Metabolic changes with increased risk of obesity and
diabetes mellitus type 2[16][11]
Sedation [11][12]

Examples
First Generation Antipsychotics (Typical
antipsychotics)

First generation antipsychotics are used to treat

schizophrenia and are often accompanied by extrapyramidal
side effects[18].

Benperidol[18] binds D2 and some serotonin receptors[19].

It's absorbed very easily and has a high first pass effect.[19]
Chlorpromazine - binds D3 with the highest affinity, but also
binds D1, D2, D4 and D5[20][21]

Chemical Structure of typical antipsychotic chlorpromazine

 Clopenthixol[18]
Droperidol is used as an antipsychotic and antiemetic.[18]
Haloperidol binds D2, D3 and D4 with the highest affinity, but
also binds D1 and D5.[18][20][21]
Fluphenazine -binds D2 and D3 with the highest affinity but
D1 and D5 as well[20][18]
Flupenthixol binds D1, D2, D3, and D5[20] and is also used as
an antidepressant.[18]
Fluspirilene[18]
Penfluridol[18]
Perazine[18]
Perphenazine[18]
Pimozide - binds D2 and D3 with high affinity, also binds D4
receptors[20][18]
Spiperone - binds D2, D3 and D4 with high affinity; can also
bind D1[18][20]
Sulpiride - binds D2 and D3[18][20] and is also used as an
antidepressant.[18]
Thioridazine - binds D2, D3 and D4 with high affinity; can also
bind D1 and D5 at higher concentrations[20]

Second Generation Antipsychotics (Atypical

Antipsychotics)
These drugs are not only dopamine antagonists at the
receptor specified, but also act on serotonin receptor
5HT2A.[22] These drugs have less extrapyramidal side effects
and are less likely to affect prolactin levels when compared to
typical antipsychotics. [23]

Amisulpride binds D2 and D3[24] and is used as an

antipsychotic, antidepressant and also treats bipolar
disorder.[22] It treats both the positive and negative
symptoms of schizophrenia. [25]
Asenapine binds D2, D3 and D4[26] and is used to treat
bipolar disorder and schizophrenia.[27] Its side effects
include weight gain but there is lower risk for orthostatic
hypotension, hyperprolactinemia
Aripriprazole binds D2 as a partial agonist but antagonizes
D3.[28] In addition, aripriprazole treats schizophrenia, bipolar
disorder (mania)[29], depression,[22] and tic disorders [28]

Clozapine

Clozapine - binds D1 and D4 with the highest affinity but still

binds D2 and D3.[30] Clozapine is unique because it is only
prescribed when treatment with at least two other
antipsychotics has failed due to its very harsh side
effects.[31] It also requires weekly white blood cell counts to
monitor potential neutropenia.[31]
Loxapine binds D2, D3 and D4 with high affinity; can also
bind D1.[32] Loxapine is often used to treat agitated and
violent patients with neuropsychiatric disorders such as
bipolar disorder and schizophrenia. [33]
Nemonapride binds D3, D4 and D5. [34]
Olanzapine binds all receptors[35] and is used to treat the
positive and negative symptoms of schizophrenia as well
as bipolar disorder and depression.[36] It has been
associated with significant weight gain.[37]
Quetiapine binds D1, D2 and D3 and can bind D4 at high
concentrations.[35] It is used to treat the positive symptoms
of schizophrenia[37], bipolar disorder and depression.[36]
Paliperidone binds D2, D3 and D4 with high affinity; can also
bind D1 and D5[38].
Remoxipridebinds D2 receptors with relatively low
affinity.[35] [39] [36]
Risperidone binds D2, D3 and D4 receptors.[36][35][38]
Risperidone not only treats the positive and negative
symptoms of schizophrenia[37] but also treats bipolar
disorder.[36]
 Tiapride blocks D2 and D3 and is used as an
antipsychotic[36]. It is also often used to treat dyskinesias,
psychomotor agitations, tics, Huntington's chorea and
alcohol dependence.[40]
Ziprasidone blocks the D2 receptor [41] and is used to treat
schizophrenia, depression and bipolar disorder.[36] There is
controversy on whether Ziprasidone treats negative
symptoms and it has well documented gastrointestinal side
effects. [37]

Dopamine antagonists used to treat nausea and

vomiting

Domperidone is a peripherally selective dopamine D2

receptor antagonist used as an antiemetic, gastroprokinetic
agent and galactagogue.
Bromopride binds enteric D2 receptors[42] and also treats
gastroparesis.[43]
Metoclopramide also treats gastroparesis[43]

Antagonists used only in research settings

Eticlopride - binds D2 and D3 with high affinity but also binds

D4[44][45][46]
Nafadotride - binds D2 and D3[43][44][45]
 Raclopride - binds D2 and D3[43][44] and can be radiolabeled
and used in PET imaging to identify disease progression in
Huntington's Disease[47]

References
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37. Mortimer AM (March 2004). "How do we choose
between atypical antipsychotics? The advantages of
amisulpride". The International Journal of
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PMID 16613552 .
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(January 1998). "Dopamine receptors: from structure to
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External links
Dopamine+antagonists at the US National Library of
Medicine Medical Subject Headings (MeSH)

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title=Dopamine_antagonist&oldid=897464639"

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