Dopamine receptor D3

DRD3
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 3PBL
Identifiers
Aliases	DRD3, D3DR, ETM1, FET1, dopamine receptor D3
External IDs	MGI: 94925 HomoloGene: 623 GeneCards: DRD3
Targeted by Drug
PF-592379, ropinirole, rotigotine, vilazodone, 7-hydroxy-2-(di-N-propylamino)tetralin, dopamine, pramipexole, quinelorane, quinpirole, apomorphine, do-687, bromocriptine, cabergoline, lisuride, pergolide, piribedil, roxindole, terguride, (+)-butaclamol, chlorpromazine, clozapine, domperidone, eticlopride, (Z)-flupentixol, haloperidol, loxapine, mesoridazine, nafadotride, nemonapride, perospirone, pimozide, prochlorperazine, promazine, raclopride, risperidone, SB-277,011-A, sertindole, spiperone, sulpiride, levosulpiride, zotepine[1]
Gene ontology Molecular function • dopamine binding • protein binding • signal transducer activity • G-protein coupled receptor activity • dopamine neurotransmitter receptor activity, coupled via Gs • dopamine neurotransmitter receptor activity • protein domain specific binding • D1 dopamine receptor binding • drug binding • dopamine neurotransmitter receptor activity, coupled via Gi/Go Cellular component • endocytic vesicle • apical part of cell • cell projection • integral component of membrane • membrane • plasma membrane • integral component of plasma membrane Biological process • negative regulation of sodium:proton antiporter activity • dopamine receptor signaling pathway • dopamine metabolic process • regulation of circadian sleep/wake cycle, sleep • negative regulation of dopamine receptor signaling pathway • positive regulation of cell proliferation • regulation of dopamine uptake involved in synaptic transmission • response to histamine • response to ethanol • prepulse inhibition • social behavior • learning • synaptic transmission, dopaminergic • positive regulation of renal sodium excretion • arachidonic acid secretion • negative regulation of protein secretion • negative regulation of transcription from RNA polymerase II promoter • gastric emptying • regulation of blood volume by renin-angiotensin • regulation of locomotion involved in locomotory behavior • cellular calcium ion homeostasis • regulation of locomotion • learning or memory • response to amphetamine • positive regulation of transcription from RNA polymerase II promoter • positive regulation of cytokinesis • signal transduction • regulation of lipid metabolic process • regulation of multicellular organism growth • visual learning • G-protein coupled receptor internalization • G-protein coupled receptor signaling pathway • regulation of dopamine secretion • negative regulation of adenylate cyclase activity • negative regulation of protein kinase B signaling • adenylate cyclase-activating dopamine receptor signaling pathway • locomotory behavior • behavioral response to cocaine • negative regulation of blood pressure • acid secretion • musculoskeletal movement, spinal reflex action • positive regulation of dopamine receptor signaling pathway • circadian regulation of gene expression • response to morphine • negative regulation of oligodendrocyte differentiation • adenylate cyclase-inhibiting dopamine receptor signaling pathway • regulation of cAMP metabolic process • positive regulation of mitotic nuclear division • response to drug • response to cocaine Sources:Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	1814	13490
Ensembl	ENSG00000151577	ENSMUSG00000022705
UniProt	P35462	P30728
RefSeq (mRNA)	NM_000796 NM_001282563 NM_001290809 NM_033658 NM_033659 NM_033660 NM_033663	NM_007877
RefSeq (protein)	NP_000787.2 NP_001269492.1 NP_001277738.1 NP_387512.3	NP_031903.1
Location (UCSC)	Chr 3: 114.13 – 114.2 Mb	Chr 16: 43.76 – 43.82 Mb
PubMed search	[2]	[3]
Wikidata

View/Edit Human

View/Edit Mouse

Dopamine receptor D₃ is a protein that in humans is encoded by the DRD3 gene.^[4][5]

This gene encodes the D₃ subtype of the dopamine receptor. The D₃ subtype inhibits adenylyl cyclase 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, drug addiction, and Parkinson's disease.^[6] 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 (NMD).^[5]

D₃ agonists like 7-OH-DPAT, pramipexole, and rotigotine, among others, display antidepressant effects in rodent models of depression.^[7][8]

Ligands

Agonists

• trans-N-{4-[4-(2,3-Dichlorophenyl)-1-piperazinyl]cyclohexyl}-3-methoxybenzamide, full agonist, > 200-fold binding selectivity over D₄, D₂, 5-HT_1A, and α1-receptors^[9]
• (-)-7-{[2-(4-Phenylpiperazin-1-yl)ethyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-ol^[10]
• 5-OH-DPAT
• 7-OH-DPAT
• 8-OH-PBZI (cis-8-Hydroxy-3-(n-propyl)-1,2,3a,4,5,9b-hexahydro-1H-benz[e]indole)
• Apomorphine (non-selective dopamine agonist)
• Bromocriptine (non-selective dopamine agonist)
• Captodiame
• CJ-1639^[11]
• compound R,R-16: 250x binding selectivity over D₂^[12]
• Dopamine (endogenous agonist)
• ES609
• FAUC 54
• FAUC 73
• PD-128,907
• PF-219,061 (extremely selective) ^[13]
• PF-592,379^[14]
• Piribedil^[15] (non-selective dopamine agonist)
• Pramipexole (non-selective dopamine agonist)
• Quinelorane (also D2 agonist)
• Quinpirole (also D2 agonist)
• Ropinirole (non-selective dopamine agonist)
• Rotigotine (non-selective dopamine agonist)

Partial agonists

• Aripiprazole (non-selective)
• BP-897^[16]
• Buspirone (non-selective)
• CJB 090
• CJ-1037 (extremely selective) ^[17]
• FAUC 460 (highly selective) ^[18]
• FAUC 346 (highly selective)^[19]
• 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
• Amisulpride (non-selective)
• Cyproheptadine (non-selective)
• PG 01037 ^[20][21]
• Domperidone (peripheral D₂ and D₃ antagonist)
• FAUC 365, silent antagonist, subtype selective^[19]
• GR-103,691
• GSK598809 (highly selective)
• Haloperidol (non-selective, blocks all dopamine receptor subtypes)
• N-(4-(4-(2,3-Dichloro- or 2-methoxyphenyl)piperazin-1-yl)butyl)heterobiarylcarboxamides^[22]
• Nafadotride
• NGB-2904^[23]
• PNU-99,194 (moderately selective over D2)
• Raclopride (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 (also D2 antagonist)
• U99194
• YQA14 (high affinity and selectivity)
• Risperidone

Interactions

Dopamine receptor D₃ has been shown to interact with CLIC6^[24] and EPB41L1.^[25]

See also

• Dopamine receptor

References

1. "Drugs that physically interact with D(3) dopamine receptor view/edit references on wikidata".
2. "Human PubMed Reference:".
3. "Mouse PubMed Reference:".
4. Le Coniat M, Sokoloff P, Hillion J, Martres MP, Giros B, Pilon C, Schwartz JC, Berger R (Oct 1991). "Chromosomal localization of the human D3 dopamine receptor gene". Hum Genet. 87 (5): 618–20. doi:10.1007/bf00209024. PMID 1916765.
5. "Entrez Gene: DRD3 dopamine receptor D3".
6. Joyce JN, Millan MJ (February 2007). "Dopamine D3 receptor agonists for protection and repair in Parkinson's disease.". Current Opinion in Pharmacology. 7 (1): 100–5. doi:10.1016/j.coph.2006.11.004. PMID 17174156.
7. Breuer ME, Groenink L, Oosting RS, Buerger E, Korte M, Ferger B, Olivier B (August 2009). "Antidepressant effects of pramipexole, a dopamine D3/D2 receptor agonist, and 7-OH-DPAT, a dopamine D3 receptor agonist, in olfactory bulbectomized rats". European Journal of Pharmacology. 616 (1-3): 134–40. doi:10.1016/j.ejphar.2009.06.029. PMID 19549514.
8. Bertaina-Anglade V, La Rochelle CD, Scheller DK (October 2006). "Antidepressant properties of rotigotine in experimental models of depression". European Journal of Pharmacology. 548 (1-3): 106–14. doi:10.1016/j.ejphar.2006.07.022. PMID 16959244.
9. Leopoldo M, Lacivita E, Colabufo NA, Berardi F, Perrone R (2006). "Synthesis and binding profile of constrained analogues of N-[4-(4-arylpiperazin-1-yl)butyl]-3-methoxybenzamides, a class of potent dopamine D3 receptor ligands". J. Pharm. Pharmacol. 58 (2): 209–18. doi:10.1211/jpp.58.2.0008. PMID 16451749.
10. Biswas S, Zhang S, Fernandez F, Ghosh B, Zhen J, Kuzhikandathil E, Reith ME, Dutta AK (2008). "Further structure-activity relationships study of hybrid 7-{[2-(4-phenylpiperazin-1-yl)ethyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-ol analogues: identification of a high-affinity D₃-preferring agonist with potent in vivo activity with long duration of action". J. Med. Chem. 51 (1): 101–17. doi:10.1021/jm070860r. PMID 18072730.
11. Chen J, Collins GT, Levant B, Woods J, Deschamps JR, Wang S (August 2011). "CJ-1639: A Potent and Highly Selective Dopamine D3 Receptor Full Agonist". ACS Med Chem Lett. 2 (8): 620–625. doi:10.1021/ml200100t. PMID 22125662.
12. Peglion JL, Poitevin C, Mannoury La Cour C, Dupuis D, Millan MJ (2009). "Modulations of the amide function of the preferential dopamine D3 agonist (R,R)-S32504: Improvements of affinity and selectivity for D3 versus D2 receptors". Bioorg. Med. Chem. Lett. 19 (8): 2133–8. doi:10.1016/j.bmcl.2009.03.015. PMID 19324548.
13. Blagg J, Allerton CM, Batchelor DV, Baxter AD, Burring DJ, Carr CL, Cook AS, Nichols CL, Phipps J, Sanderson VG, Verrier H, Wong S (2007). "Design and synthesis of a functionally selective D3 agonist and its in vivo delivery via the intranasal route". Bioorg. Med. Chem. Lett. 17 (24): 6691–6. doi:10.1016/j.bmcl.2007.10.059. PMID 17976986.
14. Collins GT, Butler P, Wayman C, Ratcliffe S, Gupta P, Oberhofer G, Caine SB (2012). "Lack of abuse potential in a highly selective dopamine D3 agonist, PF-592,379, in drug self-administration and drug discrimination in rats". Behavioural Pharmacology. 23 (3): 280–291. doi:10.1097/FBP.0b013e3283536d21. PMC 3365486. PMID 22470105.
15. Cagnotto A, Parotti L, Mennini T (October 1996). "In vitro affinity of piribedil for dopamine D3 receptor subtypes, an autoradiographic study". Eur. J. Pharmacol. 313 (1-2): 63–7. doi:10.1016/0014-2999(96)00503-1. PMID 8905329.
16. Spiller K, Xi ZX, Peng XQ, Newman AH, Ashby CR, Heidbreder C, Gaál J, Gardner EL (March 2008). "The selective dopamine D3 receptor antagonists SB-277011A and NGB 2904 and the putative partial D3 receptor agonist BP-897 attenuate methamphetamine-enhanced brain stimulation reward in rats". Psychopharmacology. 196 (4): 533–42. doi:10.1007/s00213-007-0986-6. PMID 17985117.
17. Chen J, Collins GT, Zhang J, Yang CY, Levant B, Woods J, Wang S (2008). "Design, synthesis, and evaluation of potent and selective ligands for the dopamine 3 (D3) receptor with a novel in vivo behavioral profile". J. Med. Chem. 51 (19): 5905–8. doi:10.1021/jm800471h. PMC 2662387. PMID 18785726.
18. Dörfler M, Tschammer N, Hamperl K, Hübner H, Gmeiner P (2008). "Novel D3 selective dopaminergics incorporating enyne units as nonaromatic catechol bioisosteres: synthesis, bioactivity, and mutagenesis studies". J. Med. Chem. 51 (21): 6829–38. doi:10.1021/jm800895v. PMID 18834111.
19. Bettinetti L, Schlotter K, Hübner H, Gmeiner P (2002). "Interactive SAR studies: rational discovery of super-potent and highly selective dopamine D₃ receptor antagonists and partial agonists". J. Med. Chem. 45 (21): 4594–7. doi:10.1021/jm025558r. PMID 12361386.
20. Grundt P, Carlson EE, Cao J, Bennett CJ, McElveen E, Taylor M, Luedtke RR, Newman AH (2005). "Novel heterocyclic trans olefin analogues of N-{4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butyl}arylcarboxamides as selective probes with high affinity for the dopamine D3 receptor". J. Med. Chem. 48 (3): 839–48. doi:10.1021/jm049465g. PMID 15689168.
21. Mason CW, Hassan HE, Kim KP, Cao J, Eddington ND, Newman AH, Voulalas PJ (12 March 2010). "Characterization of the Transport, Metabolism, and Pharmacokinetics of the Dopamine D3 Receptor-Selective Fluorenyl- and 2-Pyridylphenyl Amides Developed for Treatment of Psychostimulant Abuse". Journal of Pharmacology and Experimental Therapeutics. 333 (3): 854–864. doi:10.1124/jpet.109.165084. PMID 20228156.
22. Newman AH, Grundt P, Cyriac G, Deschamps JR, Taylor M, Kumar R, Ho D, Luedtke RR (2009). "N-(4-(4-(2,3-Dichloro- or 2-methoxyphenyl)piperazin-1-yl)butyl)heterobiarylcarboxamides with Functionalized Linking Chains as High Affinity and Enantioselective D3 Receptor Antagonists ( parallel) ( perpendicular)". J. Med. Chem. 52 (8): 2559–70. doi:10.1021/jm900095y. PMC 2760932. PMID 19331412.
23. Xi ZX, Gardner EL (2007). "Pharmacological actions of NGB 2904, a selective dopamine D3 receptor antagonist, in animal models of drug addiction". CNS Drug Reviews. 13 (2): 240–59. doi:10.1111/j.1527-3458.2007.00013.x. PMID 17627675.
24. Griffon N, Jeanneteau F, Prieur F, Diaz J, Sokoloff P (2003). "CLIC6, a member of the intracellular chloride channel family, interacts with dopamine D(2)-like receptors". Brain Res. Mol. Brain Res. 117 (1): 47–57. doi:10.1016/S0169-328X(03)00283-3. PMID 14499480.
25. Binda AV, Kabbani N, Lin R, Levenson R (2002). "D2 and D3 dopamine receptor cell surface localization mediated by interaction with protein 4.1N". Mol. Pharmacol. 62 (3): 507–13. doi:10.1124/mol.62.3.507. PMID 12181426.

Further reading

• Missale C, Nash SR, Robinson SW, Jaber M, Caron MG (1998). "Dopamine receptors: from structure to function.". Physiol. Rev. 78 (1): 189–225. PMID 9457173.
• Sidhu A, Niznik HB (2000). "Coupling of dopamine receptor subtypes to multiple and diverse G proteins.". Int. J. Dev. Neurosci. 18 (7): 669–77. doi:10.1016/S0736-5748(00)00033-2. PMID 10978845.
• Sokoloff P, Giros B, Martres MP, Bouthenet ML, Schwartz JC (1990). "Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics.". Nature. 347 (6289): 146–51. doi:10.1038/347146a0. PMID 1975644.
• Giros B, Martres MP, Sokoloff P, Schwartz JC (1991). "[Gene cloning of human dopaminergic D3 receptor and identification of its chromosome]". C. R. Acad. Sci. III, Sci. Vie. 311 (13): 501–8. PMID 2129115.
• Liu K, Bergson C, Levenson R, Schmauss C (1994). "On the origin of mRNA encoding the truncated dopamine D3-type receptor D3nf and detection of D3nf-like immunoreactivity in human brain.". J. Biol. Chem. 269 (46): 29220–6. PMID 7961889.
• Schmauss C, Haroutunian V, Davis KL, Davidson M (1993). "Selective loss of dopamine D3-type receptor mRNA expression in parietal and motor cortices of patients with chronic schizophrenia.". Proc. Natl. Acad. Sci. U.S.A. 90 (19): 8942–6. doi:10.1073/pnas.90.19.8942. PMC 47477. PMID 8415635.
• Griffon N, Crocq MA, Pilon C, Martres MP, Mayerova A, Uyanik G, Burgert E, Duval F, Macher JP, Javoy-Agid F, Tamminga CA, Schwartz JC, Sokoloff P (1996). "Dopamine D3 receptor gene: organization, transcript variants, and polymorphism associated with schizophrenia.". Am. J. Med. Genet. 67 (1): 63–70. doi:10.1002/(SICI)1096-8628(19960216)67:1<63::AID-AJMG11>3.0.CO;2-N. PMID 8678117.
• Staley JK, Mash DC (1996). "Adaptive increase in D3 dopamine receptors in the brain reward circuits of human cocaine fatalities.". J. Neurosci. 16 (19): 6100–6. PMID 8815892.
• Chen CH, Liu MY, Wei FC, Koong FJ, Hwu HG, Hsiao KJ (1997). "Further evidence of no association between Ser9Gly polymorphism of dopamine D3 receptor gene and schizophrenia.". Am. J. Med. Genet. 74 (1): 40–3. doi:10.1002/(SICI)1096-8628(19970221)74:1<40::AID-AJMG9>3.0.CO;2-Z. PMID 9034004.
• Gulcher JR, Jónsson P, Kong A, Kristjánsson K, Frigge ML, Kárason A, Einarsdóttir IE, Stefánsson H, Einarsdóttir AS, Sigurthoardóttir S, Baldursson S, Björnsdóttir S, Hrafnkelsdóttir SM, Jakobsson F, Benedickz J, Stefánsson K (1997). "Mapping of a familial essential tremor gene, FET1, to chromosome 3q13.". Nat. Genet. 17 (1): 84–7. doi:10.1038/ng0997-84. PMID 9288103.
• Oldenhof J, Vickery R, Anafi M, Oak J, Ray A, Schoots O, Pawson T, von Zastrow M, Van Tol HH (1998). "SH3 binding domains in the dopamine D4 receptor.". Biochemistry. 37 (45): 15726–36. doi:10.1021/bi981634+. PMID 9843378.
• Cargill M, Altshuler D, Ireland J, Sklar P, Ardlie K, Patil N, Shaw N, Lane CR, Lim EP, Kalyanaraman N, Nemesh J, Ziaugra L, Friedland L, Rolfe A, Warrington J, Lipshutz R, Daley GQ, Lander ES (1999). "Characterization of single-nucleotide polymorphisms in coding regions of human genes.". Nat. Genet. 22 (3): 231–8. doi:10.1038/10290. PMID 10391209.
• Pilla M, Perachon S, Sautel F, Garrido F, Mann A, Wermuth CG, Schwartz JC, Everitt BJ, Sokoloff P (1999). "Selective inhibition of cocaine-seeking behaviour by a partial dopamine D3 receptor agonist.". Nature. 400 (6742): 371–5. doi:10.1038/22560. PMID 10432116.
• Ilani T, Ben-Shachar D, Strous RD, Mazor M, Sheinkman A, Kotler M, Fuchs S (2001). "A peripheral marker for schizophrenia: Increased levels of D3 dopamine receptor mRNA in blood lymphocytes.". Proc. Natl. Acad. Sci. U.S.A. 98 (2): 625–8. doi:10.1073/pnas.021535398. PMC 14638. PMID 11149951.
• Lin R, Karpa K, Kabbani N, Goldman-Rakic P, Levenson R (2001). "Dopamine D2 and D3 receptors are linked to the actin cytoskeleton via interaction with filamin A.". Proc. Natl. Acad. Sci. U.S.A. 98 (9): 5258–63. doi:10.1073/pnas.011538198. PMC 33197. PMID 11320256.
• Oldenhof J, Ray A, Vickery R, Van Tol HH (2001). "SH3 ligands in the dopamine D3 receptor.". Cell. Signal. 13 (6): 411–6. doi:10.1016/S0898-6568(01)00157-7. PMID 11384839.
• Soma M, Nakayama K, Rahmutula D, Uwabo J, Sato M, Kunimoto M, Aoi N, Kosuge K, Kanmatsuse K (2002). "Ser9Gly polymorphism in the dopamine D3 receptor gene is not associated with essential hypertension in the Japanese.". Med. Sci. Monit. 8 (1): CR1–4. PMID 11796958.

External links

• "Dopamine Receptors: D₃". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.
• Receptors, Dopamine D3 at the US National Library of Medicine Medical Subject Headings (MeSH)

This article incorporates text from the United States National Library of Medicine, which is in the public domain.