Dopamine receptor D₃ is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

that in humans is encoded by the ''DRD3''

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

. This gene encodes the D₃ 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 diff ...

. 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 variously by hallucinations (typically, Auditory hallucination#Schizophrenia, hearing voices), delusions, thought disorder, disorganized thinking and behavior, and Reduced affect display, f ...

drug addiction Addiction is a neuropsychological disorder characterized by a persistent and intense urge to use a drug or engage in a behavior that produces natural reward, despite substantial harm and other negative consequences. Repetitive drug use can ...

, and

Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a neurodegenerative disease primarily of the central nervous system, affecting both motor system, motor and non-motor systems. Symptoms typically develop gradually and non-motor issues become ...

. 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 aberra ...

(NMD). On a side note, it is also the Dopamine Receptor sub-type possessing the highest binding affinity for Dopamine itself and may explain why non-

ergoline Ergoline is a core structure in many alkaloids and their synthetic derivatives. Ergoline alkaloids were first characterized in ergot. Some of these are implicated in the condition of ergotism, which can take a convulsive form or a gangrenous for ...

Dopamine Agonists A dopamine agonist is a compound that activates dopamine receptors. There are two families of dopamine receptors, D1-like and D2-like. They are all G protein-coupled receptors. D1- and D5-receptors belong to the D1-like family and the D2-like ...

are D₃-preferring

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-administer ...

pramipexole Pramipexole, sold under the brand Mirapex among others, is a medication used to treat Parkinson's disease and restless legs syndrome. In Parkinson's disease it may be used alone or together with levodopa. It is taken by mouth. Pramipexole is a ...

, 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 transderm ...

, among others, display

antidepressant Antidepressants are a class of medications used to treat major depressive disorder, anxiety disorders, chronic pain, and addiction. Common side effects of antidepressants include Xerostomia, dry mouth, weight gain, dizziness, headaches, akathi ...

effects in rodent models of depression.

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 antago ...

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

DOPAMINE-ROTIGOTINE-ROPINIROLE-PRAMIPEXOLE-SIMILARITY

Agonists

* ''trans-N''--3-methoxybenzamide, full agonist, > 200-fold binding selectivity over D₄, D₂, 5-HT_1A, and

α1-receptors The adenosine A1 receptor (A1AR) is one member of the adenosine receptor group of G protein-coupled receptors with adenosine as endogenous ligand. Biochemistry A1 receptors are implicated in sleep promotion by inhibiting wake-promoting choline ...

* (-)-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 ...

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) *

(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 malig ...

(non-selective dopamine agonist) * 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 chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...

(endogenous agonist) * ES609 * FAUC 54 * FAUC 73 * PD-128,907 *

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. It d ...

(extremely selective) *

PF-592,379 PF-592,379 is a drug developed by Pfizer which acts as a potent, functional_selectivity, selective and orally active agonist for the dopamine D3_receptor, D3 Receptor (biochemistry), receptor, which was under development as a potential medication ...

Piribedil Piribedil is an antiparkinsonian agent and piperazine derivative which acts as a D2 and D3 receptor agonist. It also has α2-adrenergic antagonist properties. Medical uses * Treatment of Parkinson's disease (PD), either as monotherapy (w ...

(non-selective dopamine agonist) *

Pramipexole Pramipexole, sold under the brand Mirapex among others, is a medication used to treat Parkinson's disease and restless legs syndrome. In Parkinson's disease it may be used alone or together with levodopa. It is taken by mouth. Pramipexole is a ...

(non-selective dopamine agonist) * Quinelorane (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). It is taken by mouth. Common side effects include sleepiness, vomiting, and dizziness. Seriou ...

(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 transderm ...

(non-selective dopamine agonist)

Partial agonists

* BP-897 *

Aripiprazole Aripiprazole, sold under the brand name Abilify, among others, is an atypical antipsychotic primarily used in the treatment of schizophrenia, bipolar disorder, and irritability associated with autism spectrum disorder; other uses include as ...

(non-selective partial agonist) *

Brexpiprazole Brexpiprazole, sold under the brand name Rexulti among others, is an atypical antipsychotic medication used for the treatment of major depressive disorder, schizophrenia, and Agitation (dementia), agitation associated with dementia due to Alzhe ...

(non-selective partial agonist) *

Buspirone Buspirone, sold under the brand name Buspar among others, is an anxiolytic, a medication primarily used to treat anxiety disorders, particularly generalized anxiety disorder (GAD). It is a serotonin 5-HT1A receptor, 5-HT1A receptor partial ag ...

(non-selective) *

Cariprazine Cariprazine, sold under the brand name Vraylar among others, is an atypical antipsychotic developed by Gedeon Richter, which is used in the treatment of schizophrenia and bipolar disorder. It is also prescribed as an add-on treatment for bip ...

* CJB 090 * CJ-1037 (extremely selective) * FAUC 460 (highly selective) * FAUC 346 (highly selective) * Pardoprunox (non-selective) * Roxindole (possibly a partial agonist at the D₃ autoreceptors, non-selective) * OS-3-106 * UH-232 * WW-III-55

Antagonists

* Most

Antipsychotics Antipsychotics, previously known as neuroleptics and major tranquilizers, are a class of psychotropic medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), principally in schizo ...

Amisulpride Amisulpride, sold under the brand names Socian and Barhemsys, is a medication used in the treatment of schizophrenia, acute psychotic episodes, depression, and nausea and vomiting. It is specifically used at lower doses intravenously to prev ...

(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 a ...

(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 ...

(peripheral D₂ and D₃ antagonist) * FAUC 365, silent

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain. * GR-103,691 *

GSK-598809 GSK-598809 is a binding selectivity, selective dopamine D3 receptor, D3 receptor receptor antagonist, antagonist that is or was under development for the treatment of substance use disorder, substance-related disorders, smoking withdrawal, and ea ...

(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 psychos ...

(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 * Mesdopetam *

Nafadotride Nafadotride is a dopamine antagonist with some selectivity for the D3 subtype (9.6-fold preference for D3 over D2).Pilla M, Perachon S, Sautel F, Garrido F, Mann A, Wermuth CG, Schwartz JC, Everitt BJ, Sokoloff P. Selective inhibition of cocaine ...

* 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-va ...

(also D₂ antagonist) * S-14,297 (selective) * S33084 * SB-277011-A, 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 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 psychosi ...

(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, as well as aggressive and self-injurious behaviors associated with autism spectrum disorder. It is t ...

Allosteric modulators

SB269652 SB269652 is an experimental dopamine D2 and D3 receptor negative allosteric modulator. It is of interest in the potential development of novel antipsychotics for treatment of schizophrenia with reduced side effects, such as extrapyramidal sympt ...

Interactions

Dopamine receptor D₃ has been shown to interact 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.

References

External links

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

Function

Animal studies

Ligands

Agonists

Partial agonists

Antagonists

Allosteric modulators

Interactions

References

Further reading

External links