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Dopamine receptor D1

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DRD1
Available structures
PDBOrtholog search:PDBeRCSB
Identifiers
AliasesDRD1,dopamine receptor D1, DADR, DRD1A
External IDsOMIM:126449;MGI:99578;HomoloGene:30992;GeneCards:DRD1;OMA:DRD1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

1812

13488

Ensembl

ENSG00000184845

ENSMUSG00000021478

UniProt

P21728

Q61616

RefSeq (mRNA)

NM_000794

NM_001291801
NM_010076

RefSeq (protein)

NP_000785

NP_001278730
NP_034206

Location (UCSC)Chr 5: 175.44 – 175.44 MbChr 13: 54.21 – 54.21 Mb
PubMedsearch[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Dopamine receptor D1,also known as DRD1. It is one of the two types of D1-like receptor family — receptors D1and D5.It is aproteinthat in humans is encoded by the DRD1 gene.[5][6][7][8]

Tissue distribution

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D1receptors are the most abundant kind ofdopamine receptorin thecentral nervous system.

Northern blotandin situ hybridizationshow that themRNA expressionof DRD1 is highest in thedorsal striatum(caudateandputamen) andventral striatum(nucleus accumbensandolfactory tubercle).[9]

Lower levels occur in thebasolateral amygdala,cerebral cortex,septum,thalamus,andhypothalamus.[9]

Function

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D1receptors regulate thememory,learning,and the growth ofneurons,also is used in the reward system and locomotor activity, mediating some behaviors and modulatingdopamine receptor D2-mediated events.[10][8]

They play a role inaddictionby facilitating thegene expression changesthat occur in thenucleus accumbensduring addiction.

They areGs coupledand can stimulate neurons by activation ofcyclic AMP-dependent protein kinase.

Production

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The DRD1 gene expresses primarily in thecaudate putamenin humans, and in thecaudate putamen,thenucleus accumbensand theolfactory tuberclein mouse. Gene expression patterns from theAllen Brain Atlasesin mouse and human can be foundhere.

Ligands

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There are a number of ligands selective for the D1receptors. To date, most of the known ligands are based ondihydrexidineor the prototypicalbenzazepinepartial agonistSKF-38393(one derivative being the prototypical antagonistSCH-23390).[11]D1receptor has a high degree ofstructural homologyto another dopamine receptor,D5,and they both bind similar drugs.[12]As a result, none of the known orthosteric ligands is selective for the D1vs. the D5receptor, but the benzazepines generally are more selective for the D1and D5receptors versus the D2-like family.[11]Some of the benzazepines have high intrinsic activity whereas others do not. In 2015 the firstpositive allosteric modulatorfor the human D1receptor was discovered byhigh-throughput screening.[13]

Agonists

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Chemical structures of selective D1receptor agonists[14][15]

Several D1receptor agonists are used clinically. These includeapomorphine,pergolide,rotigotine,andterguride.All of these drugs are preferentiallyD2-like receptoragonists.Fenoldopamis a selective D1receptorpartial agonistthat does not cross theblood-brain-barrierand is usedintravenouslyin the treatment ofhypertension.Dihydrexidineandadrogolide(ABT-431) (aprodrugofA-86929with improvedbioavailability) are the only selective, centrally activeD1-like receptoragonists that have been studied clinically in humans.[16]The selective D1agonists give profound antiparkinson effects in humans and primate models of PD, and yield cognitive enhancement in many preclinical models and a few clinical trials. The most dose-limiting feature is profoundhypotension,but the clinical development was impeded largely by lack of oral bioavailability and short duration of action.[16][17][18]In 2017, Pfizer made public information about pharmaceutically-acceptable non-catechol selective D1agonists that are in clinical development.

List of D1receptor agonists

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  • Dihydrexidine derivatives
    • A-86929– full agonist with 14-fold selectivity for D1-like receptors over D2[11][15][19]
    • Dihydrexidine– full agonist with 10-fold selectivity for D1-like receptors over D2that has been in Phase IIa clinical trials as a cognitive enhancer.[20][21]It also showed profound antiparkinson effects in MPTP-treated primates,[22]but caused profound hypotension in one early clinical trial inParkinson's disease.[11]Althoughdihydrexidinehas significant D2properties, it is highly biased at D1receptors and was used for the first demonstration offunctional selectivity[23]with dopamine receptors.[24][25]
    • Dinapsoline– full agonist with 5-fold selectivity for D1-like receptors over D2[11]
    • Dinoxyline– full agonist with approximately equal affinity for D1-like and D2receptors[11]
    • Doxanthrine– full agonist with 168-fold selectivity for D1-like receptors over D2[11]
  • Benzazepine derivatives
  • Others
    • Stepholidine– alkaloid with D1agonist and D2antagonist properties, showing antipsychotic effects
    • A-68930
    • A-77636
    • CY-208,243– high intrinsic activity partial agonist with moderate selectivity for D1-like over D2-like receptors, member ofergolineligand family likepergolideandbromocriptine.
    • SKF-89145
    • SKF-89626
    • 7,8-Dihydroxy-5-phenyl-octahydrobenzo[h]isoquinoline – extremely potent, high-affinity full agonist[27]
    • Cabergoline– weak D1agonism, highly selective for D2,and various serotonin receptors
    • Pergolide– (similar to cabergoline) weak D1agonism, highly selective for D2,and various serotonin receptors
    • Aphotoswitchableagonist of D1-like receptors (azodopa[28]) has been described that allows reversible control of dopaminergic transmission in wildtype animals.

Positive allosteric modulators

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  • DETQ –PAM[29][30][31]
  • Glovadalen(UCB-0022) – selective PAM, in phase 2 studies for Parkinson's disease
  • Mevidalen(LY-3154207) – potent and subtype selective PAM, in phase 2 studies for Lewy body dementia.[32]

Antagonists

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Manytypicalandatypical antipsychoticsare D1receptor antagonists in addition to D2receptor antagonists. Butasenapinehas shown stronger D1receptor affinity compared to other antipsychotics. No other D1receptor antagonists have been approved for clinical use.Ecopipamis a selective D1-like receptor antagonist that has been studied clinically in humans in the treatment of a variety of conditions, includingschizophrenia,cocaine abuse,obesity,pathological gambling,andTourette's syndrome,withefficacyin some of these conditions seen. The drug produced mild-to-moderate, reversibledepressionandanxietyin clinical studies however and has yet to complete development for any indication.

List of D1receptor antagonists

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Protein–protein interactions

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Dopamine receptor D1has been shown tointeractwith:

Receptor oligomers

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The D1receptor formsheteromerswith the following receptors:dopamine D2receptor,[37]dopamine D3receptor,[37][38]histamine H3receptor,[39]μ opioid receptor,[40]NMDA receptor,[37]andadenosine A1receptor.[37]

Structure

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SeveralCryoEMstructures of agonists bound to the dopamine D1 receptor complexed with the stimulatory heterotrimeric Gs protein have been determined. Agonist interact with extracellular loop 2 and extracellular regions of trans-membrane helices 2, 3, 6, and 7. Interactions between catechol-based agonists and three trans-membrane serine residues including S1985.42, S1995.43, and S2025.46 function as microswitches that are essential for receptor activation.[42]

Dopamine D1 CryoEM structure in complex with dopamine (PDB code: 7LJD), Dopamine D1 receptor in orange, dopamine in cyan, interactions are in green.[43]

See also

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References

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    Dopamine D1receptor hetero-oligomers
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[edit]

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