Dopamine Receptor D2
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Dopamine receptor D2, also known as D2R, 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 ''DRD2''
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 ...
. After work from
Paul Greengard Paul Greengard (December 11, 1925 – April 13, 2019) was an American neuroscientist best known for his work on the molecular and cellular function of neurons. In 2000, Greengard, Arvid Carlsson and Eric Kandel were awarded the Nobel Prize for ...
's lab had suggested that
dopamine receptors 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 ...
were the site of action of antipsychotic drugs, several groups, including those of Solomon Snyder and
Philip Seeman Philip Seeman, (8 February 1934 – 9 January 2021) was a Canadian schizophrenia researcher and neuropharmacologist, known for his research on dopamine receptors. Career Born in Winnipeg, Manitoba, Seeman was raised in Montreal. He received a ...
used a radiolabeled antipsychotic drug to identify what is now known as the
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 ...
D2 receptor. The dopamine D2 receptor is the main
receptor Receptor may refer to: * Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a ...
for most
antipsychotic drugs 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 oth ...
. The structure of DRD2 in complex with the atypical antipsychotic
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 ...
has been determined.


Function

D2 receptors are coupled to Gi subtype of
G protein G proteins, also known as guanine nucleotide-binding proteins, are a family of proteins that act as molecular switches inside cells, and are involved in transmitting signals from a variety of stimuli outside a cell to its interior. Their act ...
. This
G protein-coupled receptor G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...
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 ...
activity. In mice, regulation of D2R surface expression by the
neuronal calcium sensor-1 Neuronal calcium sensor-1 (NCS-1) also known as frequenin homolog (Drosophila) (freq) is a protein that is encoded by the ''FREQ'' gene in humans. NCS-1 is a member of the neuronal calcium sensor family, a class of EF hand containing calcium-myr ...
(NCS-1) in the
dentate gyrus The dentate gyrus (DG) is part of the hippocampal formation in the temporal lobe of the brain, which also includes the hippocampus and the subiculum. The dentate gyrus is part of the hippocampal trisynaptic circuit and is thought to contribute ...
is involved in exploration,
synaptic plasticity In neuroscience, synaptic plasticity is the ability of synapses to strengthen or weaken over time, in response to increases or decreases in their activity. Since memories are postulated to be represented by vastly interconnected neural circuit ...
and memory formation. Studies have shown potential roles for D2R in retrieval of fear memories in the
prelimbic cortex The dorsomedial prefrontal cortex (dmPFC or DMPFC is a section of the prefrontal cortex in some species' brain anatomy. It includes portions of Brodmann areas BA8, BA9, BA10, BA24 and BA32, although some authors identify it specifically wi ...
and in discrimination learning in the
nucleus accumbens The nucleus accumbens (NAc or NAcc; also known as the accumbens nucleus, or formerly as the ''nucleus accumbens septi'', Latin for "nucleus adjacent to the septum") is a region in the basal forebrain rostral to the preoptic area of the hypotha ...
. In flies, activation of the D2
autoreceptor An autoreceptor is a type of receptor located in the membranes of nerve cells. It serves as part of a negative feedback loop in signal transduction. It is only sensitive to the neurotransmitters or hormones released by the neuron on which the au ...
protected dopamine neurons from cell death induced by MPP+, a toxin mimicking
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 ...
pathology. While optimal dopamine levels favor D1R cognitive stabilization, it is the D2R that mediates the cognitive flexibility in humans.


Isoforms

Alternative splicing Alternative splicing, or alternative RNA splicing, or differential splicing, is an alternative splicing process during gene expression that allows a single gene to code for multiple proteins. In this process, particular exons of a gene may be ...
of this gene results in three transcript variants encoding different
isoform A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some isof ...
s. The long form (D2Lh) has the "canonical" sequence and functions as a classic post- synaptic receptor. The short form (D2Sh) is pre-synaptic and functions as an
autoreceptor An autoreceptor is a type of receptor located in the membranes of nerve cells. It serves as part of a negative feedback loop in signal transduction. It is only sensitive to the neurotransmitters or hormones released by the neuron on which the au ...
that regulates the levels of dopamine in the synaptic cleft. Agonism of D2sh receptors inhibits dopamine release; antagonism increases
dopaminergic Dopaminergic means "related to dopamine" (literally, "working on dopamine"), dopamine being a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain. Dopaminergic brain pathways facilitate d ...
release. A third D2(Longer) form differs from the canonical sequence where 270V is replaced by VVQ.


Active and inactive forms

D2R conformers are equilibrated between two full active (D2''High''R) and inactive (D2''Low''R) states, while in complex with an
agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...
and
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 ...
ligand, respectively. The monomeric inactive conformer of D2R in binding with
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 ...
was reported in 2018 ( PDB ID: 6CM4). However, the active form which is generally bound to an agonist, is not available yet and in most of the studies the
homology modeling Homology modeling, also known as comparative modeling of protein, refers to constructing an atomic-resolution model of the "''target''" protein from its amino acid sequence and an experimental three-dimensional structure of a related homologous pr ...
of the structure is implemented. The difference between the active and inactive of
G protein-coupled receptor G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...
is mainly observed as conformational changes at the cytoplasmic half of the structure, particularly at the
transmembrane domain A transmembrane domain (TMD) is a membrane-spanning protein domain. TMDs generally adopt an alpha helix topological conformation, although some TMDs such as those in porins can adopt a different conformation. Because the interior of the lipid bil ...
s (TM) 5 and 6. The conformational transitions occurred at the cytoplasmic ends are due to the coupling of
G protein G proteins, also known as guanine nucleotide-binding proteins, are a family of proteins that act as molecular switches inside cells, and are involved in transmitting signals from a variety of stimuli outside a cell to its interior. Their act ...
to the cytoplasmic loop between the TM 5 and 6. It was observed that either D2R agonist or antagonist ligands revealed better binding affinities inside the ligand-binding domain of the active D2R in comparison with the inactive state. It demonstrated that ligand-binding domain of D2R is affected by the conformational changes occurring at the cytoplasmic domains of the TM 5 and 6. In consequence, the D2R activation reflects a positive cooperation on the ligand-binding domain. In drug discovery studies in order to calculate the binding affinities of the D2R ligands inside the binding domain, it's important to work on which form of D2R. It's known that the full active and inactive states are recommended to be used for the agonist and antagonist studies, respectively. Any disordering in equilibration of D2R states, which causes problems in signal transferring between the nervous systems, may lead to diverse serious disorders, such as
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 ...
,
autism The autism spectrum, often referred to as just autism or in the context of a professional diagnosis autism spectrum disorder (ASD) or autism spectrum condition (ASC), is a neurodevelopmental condition (or conditions) characterized by difficulti ...
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 ...
. In order to control these disorders, equilibration between the D2R states is controlled by implementing of agonist and antagonist D2R ligands. In most cases, it was observed that the problems regarding the D2R states may have genetic roots and are controlled by drug therapies. So far, there is no certain treatment for these mental disorders.


Allosteric pocket and orthosteric pocket

There is an orthosteric binding site (OBS), as well as a secondary binding pocket (SBP) on the dopamine 2 receptor, and interaction with the SBP is a requirement for allosteric pharmacology. The compound SB269652 is a negative allosteric modulator of the D2R.


Oligomerization of D2R

It was observed that D2R exists in dimeric forms or higher order oligomers. There are some experimental and molecular modeling evidences that demonstrated the D2R monomers cross link from their TM 4 and TM 5 to form dimeric conformers.


Genetics

Allelic An allele (, ; ; modern formation from Greek ἄλλος ''állos'', "other") is a variation of the same sequence of nucleotides at the same place on a long DNA molecule, as described in leading textbooks on genetics and evolution. ::"The chro ...
variants: *
A-241G A- or a- may refer to: ;A-hyphen * A- (plane), a U.S. military aircraft prefix * Privative a, a prefix expressing negation * Copulative a, a prefix expressing unification ;A-minus * A−, a blood type in the ABO blood group system * A− (grade) ...
*
C132T C13 or C-13 may be: * French Defence, Encyclopaedia of Chess Openings code * C13 White Lead (Painting) Convention, 1921 * C13 grenade, the Canadian Forces designation for a M67 grenade * Autovia C-13, a highway in Catalonia in Spain * Caterpillar C1 ...
,
G423A G4 or G.IV may refer to: Transport * AEG G.IV, a German World War I heavy bomber * Allegiant Air, by IATA airline designator * Caudron G.4, a 1915 French biplane * Friedrichshafen G.IV, a 1918 German medium bomber * Gotha G.IV, a 1916 German ...
, T765C, C939T,
C957T The C957T gene polymorphism is a synonymous mutation located within the 957th base pair of the DRD2 gene. This base pair is located in exon 7. Most synonymous mutations are silent mutations, silent. However, the C957T mutation is an exception to thi ...
, and
G1101A G11 may refer to: Vehicles * BMW 7 Series (G11), a German automobile * Gribovsky G-11, a Soviet military glider of World War II * , a Royal Navy G-class submarine * , a Royal Australian Navy Q-class destroyer * Nissan Sylphy G11, a Japanese aut ...
* Cys311Ser * -141C insertion/deletion The polymorphisms have been investigated with respect to association with
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 ...
. Some researchers have previously associated the polymorphism Taq 1A (
rs1800497 The RS-18 is a reconfigured version of the Rocketdyne Lunar Module Ascent Engine (LMAE), modified to burn liquid oxygen (LOX) and liquid methane (CH4) for NASA's Exploration Systems Architecture Study (ESAS) engine testing in 2008. Developmen ...
) to the ''DRD2'' gene. However, the polymorphism resides in
exon An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequen ...
8 of the ''
ANKK1 Ankyrin repeat and kinase domain containing 1 (ANKK1) also known as protein kinase PKK2 or sugen kinase 288 (SgK288) is an enzyme that in humans is encoded by the ''ANKK1'' gene. The ANKK1 is a member of an extensive family of the Ser/Thr protei ...
'' gene. DRD2 TaqIA polymorphism has been reported to be associated with an increased risk for developing motor fluctuations but not hallucinations in Parkinson's disease. A splice variant in Dopamine receptor D2(rs1076560) was found to be associated with limb truncal
Tardive dyskinesia Tardive dyskinesia (TD) is a disorder that results in involuntary repetitive body movements, which may include grimacing, sticking out the tongue or smacking the lips. Additionally, there may be rapid jerking movements or slow writhing movemen ...
and diminished expression factor of
Positive and Negative Syndrome Scale The Positive and Negative Syndrome Scale (PANSS) is a medical scale used for measuring symptom severity of patients with schizophrenia. It was published in 1987 by Stanley Kay, Lewis Opler, and Abraham Fiszbein. It is widely used in the study of a ...
(PANSS) in
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 ...
subjects.


Ligands

Most of the older
antipsychotic 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 ...
drugs such as
chlorpromazine Chlorpromazine (CPZ), marketed under the brand names Thorazine and Largactil among others, is an antipsychotic medication. It is primarily used to treat psychotic disorders such as schizophrenia. Other uses include the treatment of bipolar dis ...
and
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 ...
are antagonists for the dopamine D2 receptor, but are, in general, very unselective, at best selective only for the "D2-like family" receptors and so binding to D2, D3 and D4, and often also to many other receptors such as those for
serotonin Serotonin () or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Its biological function is complex and multifaceted, modulating mood, cognition, reward, learning, memory, and numerous physiological processes such as vomiting and vas ...
and
histamine Histamine is an organic nitrogenous compound involved in local immune responses, as well as regulating physiological functions in the gut and acting as a neurotransmitter for the brain, spinal cord, and uterus. Since histamine was discovered in ...
, resulting in a range of side-effects and making them poor agents for scientific research. In similar manner, older dopamine agonists used for
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 ...
such as
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 maligna ...
and
cabergoline Cabergoline, sold under the brand name Dostinex among others, is a dopaminergic medication used in the treatment of high prolactin levels, prolactinomas, Parkinson's disease, and for other indications. It is taken by mouth. Cabergoline is an e ...
are poorly selective for one dopamine receptor over another, and, although most of these agents do act as D2 agonists, they affect other subtypes as well. Several selective D2
ligands In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's electro ...
are, however, now available, and this number is likely to increase as further research progresses.


Agonists

*
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 maligna ...
– full agonist *
Cabergoline Cabergoline, sold under the brand name Dostinex among others, is a dopaminergic medication used in the treatment of high prolactin levels, prolactinomas, Parkinson's disease, and for other indications. It is taken by mouth. Cabergoline is an e ...
(Dostinex) * N,N-Propyldihydrexidine – analogue of the D1/D5 agonist
dihydrexidine Dihydrexidine (DAR-0100) is a moderately selective full agonist at the dopamine D1 and D5 receptors. It has approximately 10-fold selectivity for D1 and D5 over the D2 receptor. Although dihydrexidine has some affinity for the D2 receptor, ...
; Selective for postsynaptic D2 receptor over the presynaptic D2
autoreceptor An autoreceptor is a type of receptor located in the membranes of nerve cells. It serves as part of a negative feedback loop in signal transduction. It is only sensitive to the neurotransmitters or hormones released by the neuron on which the au ...
. *
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. ...
– also D3 receptor agonist and α2–adrenergic antagonist *
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 ...
– also D3, D4 receptor agonist *
Quinagolide Quinagolide (, ), sold under the brand name Norprolac, is a selective dopamine D2 receptor agonist which is used to reduce elevated levels of prolactin (hyperprolactinemia). It has also been found to be effective in the treatment of breast pa ...
(Norprolac) *
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 ...
– affinity for D2 > D3 * Quinpirole – also D3 receptor 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. I ...
– full agonist *
Sumanirole Sumanirole (PNU-95,666) is a highly selective D2 receptor full agonist, the first of its kind to be discovered. It was developed for the treatment of Parkinson's disease and restless leg syndrome. While it has never been approved for medical us ...
– full agonist; highly selective *
Talipexole Talipexole (B-HT920, Domnin) is a dopamine agonist that is marketed as a treatment for Parkinson's Disease in Japan by Boehringer Ingelheim; it was introduced in 1996. As of December 2014 it was not approved for marketing in the US nor in Euro ...
– selective for D2 over other dopamine receptors, but also acts as α2–adrenoceptor agonist and 5-HT3 antagonist.


Partial agonists

* Aplindore *
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 ...
*
Armodafinil Armodafinil (trade name Nuvigil) is the enantiopure compound of the eugeroic modafinil (Provigil). It consists of only the (''R'')-(−)-enantiomer of the racemic modafinil. Armodafinil is produced by the pharmaceutical company Cephalon Inc. an ...
– although primarily thought to be a weak DAT inhibitor, armodafinil is also a D2 partial agonist. *
Modafinil Modafinil, sold under the brand name Provigil among others, is a central nervous system (CNS) stimulant medication used to treat sleepiness due to narcolepsy, shift work sleep disorder, and obstructive sleep apnea. While it has seen off-label ...
- The (R)-(−)-enantiomer, known as Armodafinil in its pure form *
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 ...
*
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 ...
* GSK-789,472 – Also D3 antagonist, with good selectivity over other receptors *
Ketamine Ketamine is a dissociative anesthetic used medically for induction and maintenance of anesthesia. It is also used as a recreational drug. It is one of the safest anesthetics, as, in contrast with opiates, ether, and propofol, it suppresses ne ...
(also NMDA antagonist) * 2-Phenethylamine – (also a TAAR1 agonist and GABAb antagonist with effects at AMPA receptors) *
LSD Lysergic acid diethylamide (LSD), also known colloquially as acid, is a potent psychedelic drug. Effects typically include intensified thoughts, emotions, and sensory perception. At sufficiently high dosages LSD manifests primarily mental, vi ...
– in vitro, LSD was found to be a partial agonist and potentiates dopamine-mediated prolactin secretion in lactotrophs. LSD is also a 5-HT2A agonist. * OSU-6162 – also 5-HT2A partial agonist, acts as "dopamine stabilizer" *
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 ...
(only at the D2 autoreceptors) *
RP5063 Brilaroxazine (developmental code names RP-5063 and RP-5000), also known as oxaripiprazole, is an investigational atypical antipsychotic which is under development by Reviva Pharmaceuticals for the treatment of schizophrenia and schizoaffective d ...
*
Salvinorin A Salvinorin A is the main active psychotropic molecule in '' Salvia divinorum''. Salvinorin A is considered a dissociative hallucinogen. It is structurally distinct from other naturally occurring hallucinogens (such as DMT, psilocybin, and ...
– also κ-opioid agonist. *
Memantine Memantine is a medication used to slow the progression of moderate-to-severe Alzheimer's disease. It is taken by mouth. Common side effects include headache, constipation, sleepiness, and dizziness. Severe side effects may include blood clots ...
– Also
NMDA antagonist NMDA receptor antagonists are a class of drugs that work to antagonize, or inhibit the action of, the ''N''-Methyl-D-aspartate receptor (NMDAR). They are commonly used as anesthetics for animals and humans; the state of anesthesia they induce ...


Antagonists

*
Atypical antipsychotics The atypical antipsychotics (AAP), also known as second generation antipsychotics (SGAs) and serotonin–dopamine antagonists (SDAs), are a group of antipsychotic drugs (antipsychotic drugs in general are also known as major tranquilizers and ne ...
(except aripiprazole, brexpiprazole, and any other D2 receptor partial agonists) *
Cinnarizine Cinnarizine is an antihistamine and calcium channel blocker of the diphenylmethylpiperazine group. It is prescribed for nausea and vomiting due to motion sickness or other sources such as chemotherapy, vertigo, or Ménière's disease. Cinnariz ...
* Chloroethylnorapomorphine * Desmethoxyfallypride *
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 ...
– D2 and D3 antagonist; does not cross the blood-brain barrier *
Metoclopramide Metoclopramide is a medication used for stomach and esophageal problems. It is commonly used to treat and prevent nausea and vomiting, to help with emptying of the stomach in people with delayed stomach emptying, and to help with gastroesoph ...
– Antiemetic – crosses Blood-brain Barrier – causes drug induced Parkinsonism. * Eticlopride * Fallypride *
Hydroxyzine Hydroxyzine, sold under the brand names Atarax, Vistaril and others, is an antihistamine medication. It is used in the treatment of itchiness, insomnia, anxiety, and nausea, including that due to motion sickness. It is used either by mouth or in ...
(Vistaril, Atarax) *
Itopride Itopride ( INN; brand name Ganaton) is a prokinetic benzamide derivative. These drugs inhibit dopamine and acetylcholine esterase enzyme and have a gastrokinetic effect. Itopride is indicated for the treatment of functional dyspepsia and other ...
* L-741,626 – highly selective D2 antagonist * 11C-radiolabeled
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 ...
– commonly employed in
positron emission tomography Positron emission tomography (PET) is a functional imaging technique that uses radioactive substances known as radiotracers to visualize and measure changes in Metabolism, metabolic processes, and in other physiological activities including bl ...
studies *
Typical antipsychotics Typical antipsychotics (also known as major tranquilizers, and first generation antipsychotics) are a class of antipsychotic drugs first developed in the 1950s and used to treat psychosis (in particular, schizophrenia). Typical antipsychotics ma ...
* SV 293 *
Yohimbine Yohimbine (), also known as quebrachine, is an indole alkaloid derived from the bark of the African tree ''Pausinystalia johimbe''; also from the bark of the unrelated South American tree ''Aspidosperma quebracho-blanco''. Yohimbine is an α2- ...
*
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 ...
D2 presynaptic autoreceptors (low dose) and postsynaptic D2 receptors (at higher doses) antagonist ; D2sh selective (presynaptic autoreceptors) *
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 und ...
(low doses) *
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 ...


Allosteric modulators


*
Homocysteine Homocysteine is a non-proteinogenic α-amino acid. It is a homologue of the amino acid cysteine, differing by an additional methylene bridge (-CH2-). It is biosynthesized from methionine by the removal of its terminal Cε methyl group. In the b ...
– negative
allosteric modulator In pharmacology and biochemistry, allosteric modulators are a group of substances that bind to a Receptor (biochemistry), receptor to change that receptor's response to stimulus. Some of them, like benzodiazepines, are drugs. The site that an allos ...
* PAOPA * SB-269,652 SB-269,652


Heterobivalent ligands

* 1-(6-(((''R'',''S'')-7-Hydroxychroman-2-yl)methylamino]hexyl)-3-((''S'')-1-methylpyrrolidin-2-yl)pyridinium bromide (compound 2, D2R agonist and Nicotinic acetylcholine receptor, nAChR antagonist)


Dual D2AR/ A2AAR ligands

* Dual agonists for A2AAR and D2AR receptors have been developed.


Functionally selective ligands

* UNC9994


Protein–protein interactions

The dopamine receptor D2 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
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 ...
,
PPP1R9B Neurabin-2 is a protein that in humans is encoded by the ''PPP1R9B'' gene. Spinophilin is a regulatory subunit of protein phosphatase-1 catalytic subunit (PP1; see MIM 176875) and is highly enriched in dendritic spines, specialized protrusions fr ...
and
NCS-1 Neuronal calcium sensor-1 (NCS-1) also known as frequenin homolog (Drosophila) (freq) is a protein that is encoded by the ''FREQ'' gene in humans. NCS-1 is a member of the neuronal calcium sensor family, a class of EF hand containing calcium-my ...
.


Receptor oligomers

The D2 receptor forms receptor heterodimers ''
in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...
'' (i.e., in living animals) with other
G protein-coupled receptors G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...
; these include: * D1–D2 dopamine receptor heteromer *D2adenosine A2A *D2ghrelin receptor * D2sh
TAAR1 Trace amine-associated receptor 1 (TAAR1) is a trace amine-associated receptor (TAAR) protein that in humans is encoded by the ''TAAR1'' gene. TAAR1 is an intracellular amine-activated and G protein-coupled receptor (GPCR) that is primarily ex ...
The D2 receptor has been shown to form hetorodimers ''
in vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology an ...
'' (and possibly ''in vivo'') with DRD3, DRD5, and 5-HT2A.


See also

*
Prolactin modulator A prolactin modulator is a drug which affects the hypothalamic–pituitary–prolactin axis (HPP axis) by modulating the secretion of the pituitary hormone prolactin from the anterior pituitary gland. ''Prolactin inhibitors'' suppress and ''pro ...


Explanatory notes


References


External links

* * {{Dopaminergics Dopamine receptors Biology of attention deficit hyperactivity disorder Psychopharmacology