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Dopamine receptor D4

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Title: Dopamine receptor D4  
Author: World Heritage Encyclopedia
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Subject: ABT-724, Dopamine receptor, D4, Richard Deth, A-412,997
Collection: Biology of Attention Deficit Hyperactivity Disorder, G Protein Coupled Receptors, Genes on Human Chromosome 11
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Dopamine receptor D4

Dopamine receptor D4
Symbols  ; D4DR
External IDs IUPHAR: ChEMBL: GeneCards:
RNA expression pattern
Species Human Mouse
RefSeq (mRNA)
RefSeq (protein)
Location (UCSC)
PubMed search

The dopamine receptor D4 is a G protein-coupled receptor encoded by the DRD4 gene.[1] As with other dopamine receptor subtypes, the D4 receptor is activated by the neurotransmitter dopamine. It is linked to many neurological and psychiatric conditions[2] including schizophrenia and bipolar disorder,[3] addictive behaviors,[4] Parkinsons disease,[5] and eating disorders such as anorexia nervosa.[6]

It is also a target for drugs which treat schizophrenia and Parkinson disease.[7] The D4 receptor is considered to be D2-like in which the activated receptor inhibits the enzyme adenylate cyclase, thereby reducing the intracellular concentration of the second messenger cyclic AMP.[8]


  • Genetics 1
    • 48-base pair VNTR 1.1
  • Novelty seeking 2
  • Cognitive development 3
  • Ligands 4
    • Agonists 4.1
    • Antagonists 4.2
    • Inverse agonists 4.3
  • See also 5
  • References 6
  • External links 7


The human protein is coded by the DRD4 on chromosome 11 located in 11p15.5.

There are slight variations (mutations/polymorphisms) in the human gene:

  • A 48-base pair VNTR in exon 3
  • C-521T in the promoter
  • 13-base pair deletion of bases 235 to 247 in exon 1
  • 12 base pair repeat in exon I.[9]
  • Val194Gly
  • A polymorphic tandem duplication of 120 bp

Mutations in this gene have been associated with various behavioral phenotypes, including autonomic nervous system dysfunction, attention deficit/hyperactivity disorder,[10] schizophrenia,[11] and the personality trait of novelty seeking.[12]

48-base pair VNTR

The 48-base pair VNTR in exon 3 range from 2 to 11 repeats.

DRD4-7R, the 7-repeat (7R) variant of DRD4, has been linked to a susceptibility for developing ADHD in several meta-analyses and other psychological traits and disorders.[13][14]

The frequency of the alleles varies greatly between populations, e.g., the 7-repeat version has high incidence in America and low in Asia.[15] "Long" versions of polymorphisms are the alleles with 6 to 10 repeats. 7R appears to react less strongly to dopamine molecules.[16]

The 48-base pair VNTR has been the subject of much speculation about its evolution and role in human behaviors cross-culturally. The 7R allele appears to have been selected for about 40,000 years ago.[15] In 1999 Chen and colleagues[17] observed that populations who migrated farther in the past 30,000 to 1,000 years ago had a higher frequency of 7R/long alleles. They also showed that nomadic populations had higher frequencies of 7R alleles than sedentary ones. More recently it was observed that the health status of nomadic Ariaal men was higher if they had 7R alleles. However, in recently sedentary (non-nomadic) Ariaal those with 7R alleles seemed to have slightly deteriorated health.[18]

Novelty seeking

Despite early findings of an association between the DRD4 48bp VNTR and novelty seeking (a characteristic of exploratory and excitable people),[19][20] a 2008 meta-analysis compared 36 published studies of novelty seeking and the polymorphism and found no effect. The meta-analysis of 11 studies did find that another polymorphism in the gene, the -521C/T, showed an association with novelty seeking.[21] In any case, novelty-seeking behavior is probably mediated by several genes, and the variance attributable to DRD4 by itself is not particularly large.

Cognitive development

Several studies have suggested that parenting may affect the cognitive development of children with the 7-repeat allele of DRD4.[22] Parenting that has maternal sensitivity, mindfulness, and autonomy–support at 15 months was found to alter children's executive functions at 18 to 20 months.[22] Children with poorer quality parenting were more impulsive and sensation seeking than those with higher quality parenting.[22] Higher quality parenting was associated with better effortful control in 4-year-olds.[22]


Chemical structures of representative D4-preferring ligands.


  • WAY-100635: potent full agonist, with 5-HT1A antagonistic component[23]
  • A-412,997: full agonist, > 100-fold selective over a panel of seventy different receptors and ion channels[24]
  • ABT-724 - developed for treatment of erectile dysfunction[25]
  • ABT-670 - better oral bioavailability than ABT-724[26]
  • FAUC 316: partial agonist, > 8600-fold selective over other dopamine receptor subtypes[27]
  • FAUC 299: partial agonist[27]
  • (E)-1-aryl-3-(4-pyridinepiperazin-1-yl)propanone oximes[28]
  • PIP3EA: partial agonist[29]
  • Flibanserin - partial agonist
  • PD-168,077 - D4 selective but also binds to α1A, α2C and 5HT1A
  • CP-226,269 - D4 selective but also binds to D2, D3, α2A, α2C and 5HT1A
  • Ro10-5824 - partial agonist
  • Roxindole (also D2 and D3 autoreceptor partial agonist, 5HT1A receptor agonist, serotonin reuptake inhibitor)
  • Apomorphine also adenergic and 5ht agonist, most affinity for the D4 subtype


  • A-381393: potent, subtype selective antagonist (>2700-fold)[30]
  • FAUC 213[31]
  • L-745,870[32][33]
  • L-750,667[34]
  • S 18126: also σ1 affin[35]
  • Fananserin - mixed 5-HT2A / D4 antagonist
  • Clozapine, an atypical antipsychotic
  • Buspirone, an anxiolytic

Inverse agonists

  • FAUC F41: inverse agonist, subtype selectivity of more than 3 orders of magnitude over D2 and D3[31][36]

See also


  1. ^ Van Tol HH, Bunzow JR, Guan HC, Sunahara RK, Seeman P, Niznik HB, Civelli O (Apr 1991). "Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine". Nature 350 (6319): 610–4.  
  2. ^ Ptácek R, Kuzelová H, Stefano GB (Sep 2011). "Dopamine D4 receptor gene DRD4 and its association with psychiatric disorders". Medical Science Monitor 17 (9).  
  3. ^ Domschke K (Jul 2013). "Clinical and molecular genetics of psychotic depression". Schizophrenia Bulletin 39 (4).  
  4. ^ McGeary J (Sep 2009). "The DRD4 exon 3 VNTR polymorphism and addiction-related phenotypes: a review". Pharmacology, Biochemistry, and Behavior 93 (3).  
  5. ^ Cormier F, Muellner J, Corvol JC (Apr 2013). "Genetics of impulse control disorders in Parkinson's disease". Journal of Neural Transmission 120 (4).  
  6. ^ Rask-Andersen M, Olszewski PK, Levine AS, Schiöth HB (Mar 2010). "Molecular mechanisms underlying anorexia nervosa: focus on human gene association studies and systems controlling food intake". Brain Research Reviews 62 (2).  
  7. ^ Ptáček R, Kuželová H, Stefano GB, Raboch J, Kream RM (Apr 2013). "Targeted D4 dopamine receptors: implications for drug discovery and therapeutic development". Current Drug Targets 14 (4).  
  8. ^ Neve KA, Seamans JK, Trantham-Davidson H (Aug 2004). "Dopamine receptor signaling". Journal of Receptor and Signal Transduction Research 24 (3): 165–205.  
  9. ^ Catalano M, Nobile M, Novelli E, Nöthen MM, Smeraldi E (Oct 1993). "Distribution of a novel mutation in the first exon of the human dopamine D4 receptor gene in psychotic patients". Biological Psychiatry 34 (7): 459–64.  
  10. ^ Thapar A, Langley K, Owen MJ, O'Donovan MC (Dec 2007). "Advances in genetic findings on attention deficit hyperactivity disorder". Psychological Medicine 37 (12): 1681–92.  
  11. ^ Gene Overview of All Published Schizophrenia-Association Studies for DRD4 - SzGene database at Schizophrenia Research Forum.
  12. ^ Munafò MR, Yalcin B, Willis-Owen SA, Flint J (Jan 2008). "Association of the dopamine D4 receptor (DRD4) gene and approach-related personality traits: meta-analysis and new data". Biological Psychiatry 63 (2): 197–206.  
  13. ^ Wu J, Xiao H, Sun H, Zou L, Zhu LQ (Jun 2012). "Role of dopamine receptors in ADHD: a systematic meta-analysis". Molecular Neurobiology 45 (3): 605–20.  
  14. ^ Faraone SV, Doyle AE, Mick E, Biederman J (Jul 2001). "Meta-analysis of the association between the 7-repeat allele of the dopamine D(4) receptor gene and attention deficit hyperactivity disorder". The American Journal of Psychiatry 158 (7): 1052–7.  
  15. ^ a b Wang E, Ding YC, Flodman P, Kidd JR, Kidd KK, Grady DL, Ryder OA, Spence MA, Swanson JM, Moyzis RK (May 2004). "The genetic architecture of selection at the human dopamine receptor D4 (DRD4) gene locus". American Journal of Human Genetics 74 (5): 931–44.  
  16. ^ Asghari V, Sanyal S, Buchwaldt S, Paterson A, Jovanovic V, Van Tol HH (Sep 1995). "Modulation of intracellular cyclic AMP levels by different human dopamine D4 receptor variants". Journal of Neurochemistry 65 (3): 1157–1165.  
  17. ^ Chen CS, Burton M, Greenberger E, Dmitrieva J (September 1999). "Population migration and the variation of dopamine D4 receptor (DRD4) allele frequencies around the globe". Evolution and Human Behavior 20 (5): 309–324.  
  18. ^ Eisenberg DT, Campbell B, Gray PB, Sorenson MD (2008). "Dopamine receptor genetic polymorphisms and body composition in undernourished pastoralists: an exploration of nutrition indices among nomadic and recently settled Ariaal men of northern Kenya". BMC Evolutionary Biology 8: 173.  
  19. ^ Ebstein RP, Novick O, Umansky R, Priel B, Osher Y, Blaine D, Bennett ER, Nemanov L, Katz M, Belmaker RH (Jan 1996). "Dopamine D4 receptor (D4DR) exon III polymorphism associated with the human personality trait of Novelty Seeking". Nature Genetics 12 (1): 78–80.  
  20. ^ Benjamin J, Li L, Patterson C, Greenberg BD, Murphy DL, Hamer DH (Jan 1996). "Population and familial association between the D4 dopamine receptor gene and measures of Novelty Seeking". Nature Genetics 12 (1): 81–4.  
  21. ^ Munafò MR, Yalcin B, Willis-Owen SA, Flint J (Jan 2008). "Association of the dopamine D4 receptor (DRD4) gene and approach-related personality traits: meta-analysis and new data". Biological Psychiatry 63 (2): 197–206.  
  22. ^ a b c d Posner MI, Rothbart MK, Sheese BE, Voelker P (May 2012). "Control networks and neuromodulators of early development". Developmental Psychology 48 (3): 827–35.  
  23. ^ Chemel BR, Roth BL, Armbruster B, Watts VJ, Nichols DE (Oct 2006). "WAY-100635 is a potent dopamine D4 receptor agonist". Psychopharmacology 188 (2): 244–51.  
  24. ^ Moreland RB, Patel M, Hsieh GC, Wetter JM, Marsh K, Brioni JD (Sep 2005). "A-412997 is a selective dopamine D4 receptor agonist in rats". Pharmacology, Biochemistry, and Behavior 82 (1): 140–7.  
  25. ^ Cowart M, Latshaw SP, Bhatia P, Daanen JF, Rohde J, Nelson SL, Patel M, Kolasa T, Nakane M, Uchic ME, Miller LN, Terranova MA, Chang R, Donnelly-Roberts DL, Namovic MT, Hollingsworth PR, Martino BR, Lynch JJ, Sullivan JP, Hsieh GC, Moreland RB, Brioni JD, Stewart AO (Jul 2004). "Discovery of 2-(4-pyridin-2-ylpiperazin-1-ylmethyl)-1H-benzimidazole (ABT-724), a dopaminergic agent with a novel mode of action for the potential treatment of erectile dysfunction". Journal of Medicinal Chemistry 47 (15): 3853–64.  
  26. ^ Patel MV, Kolasa T, Mortell K, Matulenko MA, Hakeem AA, Rohde JJ, Nelson SL, Cowart MD, Nakane M, Miller LN, Uchic ME, Terranova MA, El-Kouhen OF, Donnelly-Roberts DL, Namovic MT, Hollingsworth PR, Chang R, Martino BR, Wetter JM, Marsh KC, Martin R, Darbyshire JF, Gintant G, Hsieh GC, Moreland RB, Sullivan JP, Brioni JD, Stewart AO (Dec 2006). "Discovery of 3-methyl-N-(1-oxy-3',4',5',6'-tetrahydro-2'H-[2,4'-bipyridine]-1'-ylmethyl)benzamide (ABT-670), an orally bioavailable dopamine D4 agonist for the treatment of erectile dysfunction". Journal of Medicinal Chemistry 49 (25): 7450–65.  
  27. ^ a b Hübner H, Kraxner J, Gmeiner P (Nov 2000). "Cyanoindole derivatives as highly selective dopamine D(4) receptor partial agonists: solid-phase synthesis, binding assays, and functional experiments". Journal of Medicinal Chemistry 43 (23): 4563–9.  
  28. ^ Kolasa T, Matulenko MA, Hakeem AA, Patel MV, Mortell K, Bhatia P, Henry R, Nakane M, Hsieh GC, Terranova MA, Uchic ME, Miller LN, Chang R, Donnelly-Roberts DL, Namovic MT, Hollingsworth PR, Martino B, El Kouhen O, Marsh KC, Wetter JM, Moreland RB, Brioni JD, Stewart AO (Aug 2006). "1-aryl-3-(4-pyridine-2-ylpiperazin-1-yl)propan-1-one oximes as potent dopamine D4 receptor agonists for the treatment of erectile dysfunction". Journal of Medicinal Chemistry 49 (17): 5093–109.  
  29. ^ Enguehard-Gueiffier C, Hübner H, El Hakmaoui A, Allouchi H, Gmeiner P, Argiolas A, Melis MR, Gueiffier A (Jun 2006). "2-[(4-phenylpiperazin-1-yl)methyl]imidazo(di)azines as selective D4-ligands. Induction of penile erection by 2-[4-(2-methoxyphenyl)piperazin-1-ylmethyl]imidazo[1,2-a]pyridine (PIP3EA), a potent and selective D4 partial agonist". Journal of Medicinal Chemistry 49 (13): 3938–47.  
  30. ^ Nakane M, Cowart MD, Hsieh GC, Miller L, Uchic ME, Chang R, Terranova MA, Donnelly-Roberts DL, Namovic MT, Miller TR, Wetter JM, Marsh K, Stewart AO, Brioni JD, Moreland RB (Jul 2005). "2-[4-(3,4-Dimethylphenyl)piperazin-1-ylmethyl]-1H benzoimidazole (A-381393), a selective dopamine D4 receptor antagonist". Neuropharmacology 49 (1): 112–21.  
  31. ^ a b Prante O, Tietze R, Hocke C, Löber S, Hübner H, Kuwert T, Gmeiner P (Mar 2008). "Synthesis, radiofluorination, and in vitro evaluation of pyrazolo[1,5-a]pyridine-based dopamine D4 receptor ligands: discovery of an inverse agonist radioligand for PET". Journal of Medicinal Chemistry 51 (6): 1800–10.  
  32. ^ Kulagowski JJ, Broughton HB, Curtis NR, Mawer IM, Ridgill MP, Baker R, Emms F, Freedman SB, Marwood R, Patel S, Patel S, Ragan CI, Leeson PD (May 1996). "3-((4-(4-Chlorophenyl)piperazin-1-yl)-methyl)-1H-pyrrolo-2,3-b-pyridine: an antagonist with high affinity and selectivity for the human dopamine D4 receptor". Journal of Medicinal Chemistry 39 (10): 1941–2.  
  33. ^ Patel S, Freedman S, Chapman KL, Emms F, Fletcher AE, Knowles M, Marwood R, Mcallister G, Myers J, Curtis N, Kulagowski JJ, Leeson PD, Ridgill M, Graham M, Matheson S, Rathbone D, Watt AP, Bristow LJ, Rupniak NM, Baskin E, Lynch JJ, Ragan CI (Nov 1997). "Biological profile of L-745,870, a selective antagonist with high affinity for the dopamine D4 receptor". The Journal of Pharmacology and Experimental Therapeutics 283 (2): 636–47.  
  34. ^ Patel S, Patel S, Marwood R, Emms F, Marston D, Leeson PD, Curtis NR, Kulagowski JJ, Freedman SB (Dec 1996). "Identification and pharmacological characterization of [125I]L-750,667, a novel radioligand for the dopamine D4 receptor". Molecular Pharmacology 50 (6): 1658–64.  
  35. ^ Millan MJ, Newman-Tancredi A, Brocco M, Gobert A, Lejeune F, Audinot V, Rivet JM, Schreiber R, Dekeyne A, Spedding M, Nicolas JP, Peglion JL (Oct 1998). "S 18126 ([2-[4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)piperazin-1-yl methyl]indan-2-yl]), a potent, selective and competitive antagonist at dopamine D4 receptors: an in vitro and in vivo comparison with L 745,870 (3-(4-[4-chlorophenyl]piperazin-1-yl)methyl-1H-pyrrolo[2, 3b]pyridine) and raclopride". The Journal of Pharmacology and Experimental Therapeutics 287 (1): 167–86.  
  36. ^ Lanig H, Utz W, Gmeiner P (Apr 2001). "Comparative molecular field analysis of dopamine D4 receptor antagonists including 3-[4-(4-chlorophenyl)piperazin-1-ylmethyl]pyrazolo[1,5-a]pyridine (FAUC 113), 3-[4-(4-chlorophenyl)piperazin-1-ylmethyl]-1H-pyrrolo-[2,3-b]pyridine (L-745,870), and clozapine". Journal of Medicinal Chemistry 44 (8): 1151–7.  

External links

  • "4"Dopamine Receptors: D. IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. 
  • Gene4Current Research on the DRD
  • Receptors, Dopamine D4 at the US National Library of Medicine Medical Subject Headings (MeSH)
  • Marisa Wilson. "Are you a thrill seeker??". Davidson College. Retrieved 2008-04-05. 
  • "The D4DR Gene". D4DR Club. Retrieved 2008-04-05. 

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