Dopamine receptor D₃ 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 D₃ subtype of the dopamine receptor. The D₃ 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, 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 aberrant ...

(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. D₃ 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 ...

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, 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

D₃ 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 D₄, D₂, 5-HT_1A, and α1-receptors * (-)-7--5,6,7,8-tetrahydronaphthalen-2-ol *

5-OH-DPAT 5-OH-DPAT is a synthetic compound that acts as a dopamine receptor agonist with selectivity for the D2 receptor and D3 receptor subtypes. Only the (''S'')-enantiomer is active as an agonist, with the (''R'')-enantiomer being a weak antagonist at ...

* Pergolide *

8-OH-PBZI 8-OH-PBZI is a drug used in scientific research which acts as a potent and selective agonist for the dopamine D3 receptor Receptor may refer to: * Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, prod ...

(cis-8-Hydroxy-3-(n-propyl)-1,2,3a,4,5,9b-hexahydro-1H-benz ndole) * Apomorphine (non-selective dopamine agonist) * Bromocriptine (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 captodiame ...

* CJ-1639 * compound ''R,R''-16: 250x binding selectivity over D₂ *

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 * FAUC 54 * FAUC 73 * PD-128,907 *

PF-219,061 PF-219,061 is a drug that was under drug development, development by Pfizer which acts as a potent and highly functional_selectivity, selective agonist for the dopamine D3_receptor, D3 Receptor (biochemistry), receptor. It was under development as ...

(extremely selective) * PF-592,379 * Piribedil (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 (also D2 agonist) *

Quinpirole Quinpirole is a psychoactive drug and research chemical which acts as a selective D2 and D3 receptor agonist. It is used in scientific research. Quinpirole has been shown to increase locomotion and sniffing behavior in mice treated with it. At ...

(also D2 agonist) * Ropinirole (non-selective dopamine agonist) * Rotigotine (non-selective dopamine agonist)

Partial agonists

* Aripiprazole (non-selective) *

BP-897 BP-897 is a drug used in scientific research which acts as a potent selective dopamine D3 receptor partial agonist with an in vitro intrinsic activity of ~0.6 and ~70x greater affinity for D3 over D2 receptors and is suspected to have partial ag ...

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 (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 Pardoprunox (INN) (code name SLV-308) is an antiparkinsonian drug developed by Solvay for the treatment of Parkinson's disease that reached phase III clinical trials before being discontinued.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 Psychiatric medication, psychotropic medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), principally in schizophrenia but ...

* Amisulpride (non-selective) * Cyproheptadine (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 D₂ and D₃ 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 (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 Nafadotride is a dopamine antagonist A dopamine antagonist, also known as an anti-dopaminergic and a dopamine receptor antagonist (DRA), is a type of drug which blocks dopamine receptors by receptor antagonism. Most antipsychotics are dopami ...

* 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 SB-277,011A is a drug which acts as a potent and selective dopamine D3 receptor antagonist, which is around 80-100x selective for D3 over D2, and lacks any partial agonist activity. SB-277,011A is used in the study of addiction to stimulant dru ...

, selective D₃ antagonist, 80x selectivity over D₂ 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 (also D2 antagonist) * U99194 * YQA14 (high affinity and selectivity) * Risperidone

Interactions

Dopamine receptor D₃ 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 Chloride intracellular channel protein 6 is a protein that in humans is encoded by the ''CLIC6'' gene. The CLIC6 gene encodes a member of the chloride intracellular channel family of proteins. The gene is part of a large triplicated region found ...

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.

References

External links

* * {{G protein-coupled receptors Dopamine receptors Biology of attention deficit hyperactivity disorder