Dopamine receptor D
3 is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
that in humans is encoded by the ''DRD3''
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
.
This gene encodes the D
3 subtype of the
dopamine receptor
Dopamine receptors are a class of G protein-coupled receptors that are prominent in the vertebrate central nervous system (CNS). Dopamine receptors activate different effectors through not only G-protein coupling, but also signaling through diffe ...
. The D
3 subtype inhibits
adenylyl cyclase
Adenylate cyclase (EC 4.6.1.1, also commonly known as adenyl cyclase and adenylyl cyclase, abbreviated AC) is an enzyme with systematic name ATP diphosphate-lyase (cyclizing; 3′,5′-cyclic-AMP-forming). It catalyzes the following reaction:
:A ...
through inhibitory G-proteins. This receptor is expressed in phylogenetically older regions of the brain, suggesting that this receptor plays a role in cognitive and emotional functions. It is a target for drugs which treat
schizophrenia
Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social withdra ...
,
drug addiction
Addiction is a neuropsychological disorder characterized by a persistent and intense urge to engage in certain behaviors, one of which is the usage of a drug, despite substantial harm and other negative consequences. Repetitive drug use of ...
, and
Parkinson's disease
Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...
. Alternative splicing of this gene results in multiple transcript variants that would encode different isoforms, although some variants may be subject to
nonsense-mediated decay
Nonsense-mediated mRNA decay (NMD) is a surveillance pathway that exists in all eukaryotes. Its main function is to reduce errors in gene expression by eliminating mRNA transcripts that contain premature stop codons. Translation of these aberran ...
(NMD).
Function
Alpha-synuclein (α-Syn) aggregation via Lewy bodies inclusion, a pathogenic signature exclusively present in PD patients, is decreased by D3 agonists while DA content is elevated by inhibiting DA reuptake and breakdown. The regulation of α-Syn aggregation and clearance enhances brain-derived neurotrophic factor (BDNF) secretion, which ultimately ameliorates neuroinflammation and oxidative stress while promoting neurogenesis and interacting with other DA receptors.
D
3 agonists like
7-OH-DPAT
7-OH-DPAT is a synthetic compound that acts as a dopamine receptor agonist with reasonable selectivity for the D3 receptor subtype, and low affinity for serotonin receptors, unlike its structural isomer 8-OH-DPAT. 7-OH-DPAT is self-administered i ...
,
pramipexole
Pramipexole, sold under the brand Mirapex among others, is medication used to treat Parkinson's disease (PD) and restless legs syndrome (RLS). In Parkinson's disease it may be used alone or together with levodopa. It is taken by mouth. Pramipex ...
, and
rotigotine
Rotigotine, sold under the brand name Neupro among others, is a dopamine agonist of the non-ergoline class of medications indicated for the treatment of Parkinson's disease and restless legs syndrome. It is formulated as a once-daily transdermal ...
, among others, display
antidepressant
Antidepressants are a class of medication used to treat major depressive disorder, anxiety disorders, chronic pain conditions, and to help manage addictions. Common side-effects of antidepressants include dry mouth, weight gain, dizziness, hea ...
effects in rodent models of
depression.
Apomorphine has the ability to help PD patients with their cognition awareness. In addition to having antidepressant properties such as regulating the depression-like behaviors and depression development, pramipexole has the capability to prevent and slow down cell apoptosis as well as to restore damaged neural networks and connections while rotigotine help PD patients to attenuates hyperpyrexia syndrome and schizophrenia.
Animal studies
D
3 agonists have been shown to disrupt
prepulse inhibition of startle (PPI), a cross-species measure that recapitulates deficits in sensorimotor gating in neuropsychiatric disorders such as schizophrenia.
In contrast, D3-preferring antagonists have antipsychotic-like profiles in measures of PPI in rats.
Ligands
Agonists
* ''trans-N''-
-3-methoxybenzamide, full agonist, > 200-fold binding selectivity over D
4, D
2,
5-HT1A, and
α1-receptors
* (-)-7-
-5,6,7,8-tetrahydronaphthalen-2-ol
*
5-OH-DPAT
*
7-OH-DPAT
7-OH-DPAT is a synthetic compound that acts as a dopamine receptor agonist with reasonable selectivity for the D3 receptor subtype, and low affinity for serotonin receptors, unlike its structural isomer 8-OH-DPAT. 7-OH-DPAT is self-administered i ...
*
Pergolide
Pergolide, sold under the brand name Permax and Prascend (veterinary) among others, is an ergoline-based dopamine receptor agonist used in some countries for the treatment of Parkinson's disease. Parkinson's disease is associated with reduced do ...
*
8-OH-PBZI (cis-8-Hydroxy-3-(n-propyl)-1,2,3a,4,5,9b-hexahydro-1H-benz
ndole)
*
Apomorphine
Apomorphine, sold under the brand name Apokyn among others, is a type of aporphine having activity as a non- selective dopamine agonist which activates both D2-like and, to a much lesser extent, D1-like receptors. It also acts as an antag ...
(non-selective dopamine agonist)
*
Bromocriptine
Bromocriptine, originally marketed as Parlodel and subsequently under many brand names, is an ergoline derivative and dopamine agonist that is used in the treatment of pituitary tumors, Parkinson's disease, hyperprolactinaemia, neuroleptic ...
(non-selective dopamine agonist)
*
Captodiame
Captodiame (INN), also known as captodiamine, is an antihistamine sold under the trade names Covatine, Covatix, and Suvren which is used as a sedative and anxiolytic. The structure is related to diphenhydramine.
A 2004 study suggested captodiam ...
*
CJ-1639
* compound ''R,R''-16: 250x binding selectivity over D
2
*
Dopamine
Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic compound, organic chemical of the catecholamine and phenethylamine families. Dopamine const ...
(endogenous agonist)
*
ES609
ECMAScript (; ES) is a JavaScript standard intended to ensure the interoperability of web pages across different browsers. It is standardized by Ecma International in the documenECMA-262
ECMAScript is commonly used for client-side scripting ...
* FAUC 54
* FAUC 73
*
PD-128,907
PD-128,907 is a drug used in scientific research which acts as a potent and selective agonist for the dopamine D2 and D3 receptors. It is used for studying the role of these receptors in the brain, in roles such as inhibitory autoreceptors that ...
*
PF-219,061
PF-219,061 is a drug that was under development by Pfizer which acts as a potent and highly selective agonist for the dopamine D3 receptor. It was under development as a potential medication for the treatment of female sexual dysfunction. I ...
(extremely selective)
*
PF-592,379
PF-592,379 is a drug developed by Pfizer which acts as a potent, selective and orally active agonist for the dopamine D3 receptor, which is under development as a potential medication for the treatment of female sexual dysfunction and male ere ...
*
Piribedil
Piribedil (trade names Pronoran, Trivastal Retard, Trastal, Trivastan, Clarium and others) is an antiparkinsonian agent and piperazine derivative which acts as a D2 and D3 receptor agonist. It also has α2-adrenergic antagonist properties.
...
(non-selective dopamine agonist)
*
Pramipexole
Pramipexole, sold under the brand Mirapex among others, is medication used to treat Parkinson's disease (PD) and restless legs syndrome (RLS). In Parkinson's disease it may be used alone or together with levodopa. It is taken by mouth. Pramipex ...
(non-selective dopamine agonist)
*
Quinelorane
Quinelorane is a drug which acts as a dopamine agonist for the D2 and D3 receptor.
See also
* Quinpirole
References
Dopamine agonists
Aminopyrimidines
{{nervous-system-drug-stub ...
(also D2 agonist)
*
Quinpirole (also D2 agonist)
*
Ropinirole
Ropinirole, sold under the brand name Requip among others, is a medication used to treat Parkinson's disease (PD) and restless legs syndrome (RLS). In PD the dose needs to be adjusted to the effect and treatment should not be suddenly stopped. ...
(non-selective dopamine agonist)
*
Rotigotine
Rotigotine, sold under the brand name Neupro among others, is a dopamine agonist of the non-ergoline class of medications indicated for the treatment of Parkinson's disease and restless legs syndrome. It is formulated as a once-daily transdermal ...
(non-selective dopamine agonist)
Partial agonists
*
Aripiprazole
Aripiprazole, sold under the brand names Abilify and Aristada among others, is an atypical antipsychotic. It is primarily used in the treatment of schizophrenia and bipolar disorder. Other uses include as an add-on treatment in major depressiv ...
(non-selective)
*
BP-897
*
Brexpiprazole
Brexpiprazole, sold under the brand name Rexulti among others, is an atypical antipsychotic. It is a dopamine D2 receptor partial agonist and has been described as a "serotonin–dopamine activity modulator" (SDAM). The drug was approved by th ...
(non-selective)
*
Buspirone
Buspirone, sold under the brand name Buspar, among others, is a medication primarily used to treat anxiety disorders, particularly generalized anxiety disorder. Benefits support its short-term use. It is taken by mouth, and it may take up to fo ...
(non-selective)
*
Cariprazine
Cariprazine, sold under the brand names Vraylar and Reagila among others, is an on oral atypical antipsychotic originated by Gedeon Richter, which is used in the treatment of schizophrenia, bipolar mania, and bipolar depression. It acts prim ...
*
CJB 090
* CJ-1037 (extremely selective)
* FAUC 460 (highly selective)
* FAUC 346 (highly selective)
*
Pardoprunox (non-selective)
*
Roxindole
Roxindole (EMD-49,980) is a dopaminergic and serotonergic drug which was originally developed by Merck KGaA for the treatment of schizophrenia. In clinical trials its antipsychotic efficacy was only modest but it was unexpectedly found to produc ...
(possibly a partial agonist at the D3 autoreceptors, non-selective)
*
OS-3-106
*
UH-232
UH-232 ((+)-UH232) is a drug which acts as a subtype selective mixed agonist-antagonist for dopamine receptors, acting as a weak partial agonist at the D3 subtype, and an antagonist at D2Sh autoreceptors on dopaminergic nerve terminals. This cau ...
*
WW-III-55
Antagonists
* Most
Antipsychotics
Antipsychotics, also known as neuroleptics, are a class of psychotropic medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), principally in schizophrenia but also in a range of ...
*
Amisulpride
Amisulpride is an antiemetic and antipsychotic medication used at lower doses intravenously to prevent and treat postoperative nausea and vomiting; and at higher doses by mouth to treat schizophrenia and acute psychotic episodes. It is sold un ...
(non-selective)
*
Cyproheptadine
Cyproheptadine, sold under the brand name Periactin among others, is a first-generation antihistamine, first-generation antihistamine with additional anticholinergic, antiserotonergic, and local anesthetic properties.
It was patented in 1959 an ...
(non-selective)
* PG 01037
*
Domperidone
Domperidone, sold under the brand name Motilium among others, is a dopamine antagonist medication which is used to treat nausea and vomiting and certain gastrointestinal problems like gastroparesis (delayed gastric emptying). It raises the le ...
(peripheral D
2 and D
3 antagonist)
* FAUC 365, silent
antagonist
An antagonist is a character in a story who is presented as the chief foe of the protagonist.
Etymology
The English word antagonist comes from the Greek ἀνταγωνιστής – ''antagonistēs'', "opponent, competitor, villain, enemy, riv ...
, subtype selective
*
GR-103,691
*
GSK598809 (highly selective)
*
Haloperidol
Haloperidol, sold under the brand name Haldol among others, is a typical antipsychotic medication. Haloperidol is used in the treatment of schizophrenia, tics in Tourette syndrome, mania in bipolar disorder, delirium, agitation, acute psychosi ...
(non-selective, blocks all dopamine receptor subtypes, though D3 with the strongest affinity)
* N-(4-(4-(2,3-Dichloro- or 2-methoxyphenyl)piperazin-1-yl)butyl)heterobiarylcarboxamides
*
Nafadotride
*
NGB-2904
*
PNU-99,194
PNU-99,194(A) (or U-99,194(A)) is a drug which acts as a moderately selective D3 receptor antagonist with ~15-30-fold preference for D3 over the D2 subtype. Though it has substantially greater preference for D3 over D2, the latter receptor doe ...
(moderately selective over D2)
*
Raclopride
Raclopride is a typical antipsychotic. It acts as a selective antagonist on D2 dopamine receptors. It has been used in trials studying Parkinson Disease.
Its selectivity to the cerebral D2 receptors is characterized by its respective Ki-valu ...
(also D2 antagonist)
*
S-14,297 (selective)
*
S33084
*
SB-277011-A, selective D
3 antagonist, 80x selectivity over D
2 with no partial agonist effects, used in drug addiction research as a potential therapy for addiction to several different drugs
*
SR 21502 (highly selective)
*
Sulpiride
Sulpiride, sold under the brand name Dogmatil among others, is an atypical antipsychotic (although some texts have referred to it as a typical antipsychotic) medication of the benzamide class which is used mainly in the treatment of psychosis ...
(also D2 antagonist)
*
U99194
*
YQA14 (high affinity and selectivity)
*
Risperidone
Risperidone, sold under the brand name Risperdal among others, is an atypical antipsychotic used to treat schizophrenia and bipolar disorder. It is taken either by mouth or by injection (subcutaneous or intramuscular). The injectable versions ...
Interactions
Dopamine receptor D
3 has been shown to
interact
Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...
with
CLIC6 and
EPB41L1
Band 4.1-like protein 1 is a protein that in humans is encoded by the ''EPB41L1'' gene.
Function
Erythrocyte membrane protein band 4.1 (EPB41) is a multifunctional protein that mediates interactions between the erythrocyte cytoskeleton and the ...
.
DRD3 Ser9Gly polymorphism(rs6280), which is a single nucleotide polymorphism (SNP) with variant base C/T is linked to variation in PD such as depression severity, impulse control disorders, behavioral addiction and aberrant decision-making.
See also
*
Dopamine receptor
Dopamine receptors are a class of G protein-coupled receptors that are prominent in the vertebrate central nervous system (CNS). Dopamine receptors activate different effectors through not only G-protein coupling, but also signaling through diffe ...
References
Further reading
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External links
*
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{{G protein-coupled receptors
Dopamine receptors
Biology of attention deficit hyperactivity disorder