Dopamine receptor D4
|Dopamine receptor D4|
|External IDs||IUPHAR: ChEMBL: GeneCards:|
|RNA expression pattern|
The dopamine receptor D4 is a G protein-coupled receptor encoded by the DRD4 gene. As with other dopamine receptor subtypes, the D4 receptor is activated by the neurotransmitter dopamine. It is linked to many neurological and psychiatric conditions including schizophrenia, Parkinsons disease, bipolar disorder, addictive behaviors, and eating disorders such as anorexia nervosa, bulimia nervosa and binge eating.
It is also a target for drugs which treat schizophrenia and Parkinson disease. 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.
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.
- 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, schizophrenia, and the personality trait of novelty seeking.
48-base pair VNTR 
The 48-base pair VNTR in exon 3 range from 2 to 11 repeats. The frequency of the alleles varies greatly between populations, e.g., the 7-repeat version has high incidence in America and low in Asia. "Long" versions of polymorphisms are the alleles with 6 to 10 repeats. 7R appears to react less strongly to dopamine molecules.
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. In 1999 Chen and colleagues 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.
Novelty seeking 
Despite early findings of an association between the DRD4 48bp VNTR and novelty seeking (a characteristic of exploratory and excitable people), 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. 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. 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. Children with poorer quality parenting were more impulsive and sensation seeking than those with higher quality parenting. Higher quality parenting was associated with better effortful control in 4-year-olds.
- WAY-100635: potent full agonist, with 5-HT1A antagonistic component
- A-412,997: full agonist, > 100-fold selective over a panel of seventy different receptors and ion channels
- ABT-724 - developed for treatment of erectile dysfunction
- ABT-670 - better oral bioavailability than ABT-724
- FAUC 316: partial agonist, > 8600-fold selective over other dopamine receptor subtypes
- FAUC 299: partial agonist
- (E)-1-aryl-3-(4-pyridinepiperazin-1-yl)propanone oximes
- PIP3EA: partial agonist
- 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
- A-381393: potent, subtype selective antagonist (>2700-fold)
- FAUC 213
- S 18126: also σ1 affin
- Fananserin - mixed 5-HT2A / D4 antagonist
- Clozapine, an atypical antipsychotic
Inverse agonists 
- FAUC F41: inverse agonist, subtype selectivity of more than 3 orders of magnitude over D2 and D3
See also 
- Van Tol HH, Bunzow JR, Guan HC, Sunahara RK, Seeman P, Niznik HB, Civelli O (April 1991). "Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine". Nature 350 (6319): 610–4. doi:10.1038/350610a0. PMID 1840645.
- Neve KA, Seamans JK, Trantham-Davidson H (August 2004). "Dopamine receptor signaling". J. Recept. Signal Transduct. Res. 24 (3): 165–205. doi:10.1081/RRS-200029981. PMID 15521361.
- Catalano M, Nobile M, Novelli E, Nöthen MM, Smeraldi E (October 1993). "Distribution of a novel mutation in the first exon of the human dopamine D4 receptor gene in psychotic patients". Biol. Psychiatry 34 (7): 459–64. doi:10.1016/0006-3223(93)90236-7. PMID 8268330.
- Thapar A, Langley K, Owen MJ, O'Donovan MC (December 2007). "Advances in genetic findings on attention deficit hyperactivity disorder". Psychol Med 37 (12): 1681–92. doi:10.1017/S0033291707000773. PMID 17506925.
- Gene Overview of All Published Schizophrenia-Association Studies for DRD4 - SzGene database at Schizophrenia Research Forum.
- Munafò MR, Yalcin B, Willis-Owen SA, Flint J (January 2008). "Association of the dopamine D4 receptor (DRD4) gene and approach-related personality traits: meta-analysis and new data". Biol. Psychiatry 63 (2): 197–206. doi:10.1016/j.biopsych.2007.04.006. PMID 17574217.
- 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". Am. J. Hum. Genet. 74 (5): 931–44. doi:10.1086/420854. PMC 1181986. PMID 15077199.
- Asghari V, Sanyal S, Buchwaldt S, Paterson A, Jovanovic V, Van Tol HH (September 1995). "Modulation of intracellular cyclic AMP levels by different human dopamine D4 receptor variants". J Neurochem 65 (3): 1157–1165. doi:10.1046/j.1471-4159.1995.65031157.x. PMID 7643093.
- Faraone SV, Doyle AE, Mick E, Biederman J (July 2001). "Meta-analysis of the association between the 7-repeat allele of the dopamine D(4) receptor gene and attention deficit hyperactivity disorder". American Journal of Psychiatry 158 (7): 1052–7. doi:10.1176/appi.ajp.158.7.1052. PMID 11431226.
- 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. doi:10.1016/S1090-5138(99)00015-X.
- 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 Evol. Biol. 8: 173. doi:10.1186/1471-2148-8-173. PMC 2440754. PMID 18544160.
- Ebstein RP, Novick O, Umansky R, Priel B, Osher Y, Blaine D, Bennett ER, Nemanov L, Katz M, Belmaker RH (January 1996). "Dopamine D4 receptor (D4DR) exon III polymorphism associated with the human personality trait of Novelty Seeking". Nat. Genet. 12 (1): 78–80. doi:10.1038/ng0196-78. PMID 8528256.
- Benjamin J, Li L, Patterson C, Greenberg BD, Murphy DL, Hamer DH (January 1996). "Population and familial association between the D4 dopamine receptor gene and measures of Novelty Seeking". Nat. Genet. 12 (1): 81–4. doi:10.1038/ng0196-81. PMID 8528258.
- Munafo MR, Yalcin B, Willis-Owen SA, Flint J. (2008). "Association of the dopamine D4 receptor (DRD4) gene and approach-related personality traits: meta-analysis and new data". Biol Psychiatry 63 (2): 197–206. doi:10.1016/j.biopsych.2007.04.006. PMID 17574217.
- Posner MI, Rothbart MK, Sheese BE, Voelker P (May 2012). "Control networks and neuromodulators of early development". Dev Psychol 48 (3): 827–35. doi:10.1037/a0025530. PMID 21942663.
- Chemel BR, Roth BL, Armbruster B, Watts VJ, Nichols DE (2006). "WAY-100635 is a potent dopamine D4 receptor agonist". Psychopharmacology (Berl.) 188 (2): 244–51. doi:10.1007/s00213-006-0490-4. PMID 16915381.
- Moreland RB, Patel M, Hsieh GC, Wetter JM, Marsh K, Brioni JD (2005). "A-412997 is a selective dopamine D4 receptor agonist in rats". Pharmacol. Biochem. Behav. 82 (1): 140–7. doi:10.1016/j.pbb.2005.08.001. PMID 16153699.
- 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 (July 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. doi:10.1021/jm030505a. PMID 15239663.
- Patel MV, Kolasa T, Mortell K, et al. (December 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". J. Med. Chem. 49 (25): 7450–65. doi:10.1021/jm060662k. PMID 17149874.
- Hübner H, Kraxner J, Gmeiner P (2000). "Cyanoindole derivatives as highly selective dopamine D4 receptor partial agonists: solid-phase synthesis, binding assays, and functional experiments". J. Med. Chem. 43 (23): 4563–9. doi:10.1021/jm0009989. PMID 11087581.
- Kolasa T, Matulenko MA, Hakeem AA, et al. (August 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". J. Med. Chem. 49 (17): 5093–109. doi:10.1021/jm060279f. PMID 16913699.
- Enguehard-Gueiffier C, Hübner H, El Hakmaoui A, et al. (June 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". J. Med. Chem. 49 (13): 3938–47. doi:10.1021/jm060166w. PMID 16789750.
- Nakane M, Cowart MD, Hsieh GC, et al. (July 2005). "2-[4-(3,4-Dimethylphenyl)piperazin-1-ylmethyl]-1H benzoimidazole (A-381393), a selective dopamine D4 receptor antagonist". Neuropharmacology 49 (1): 112–21. doi:10.1016/j.neuropharm.2005.02.004. PMID 15992586.
- Prante O, Tietze R, Hocke C, Löber S, Hübner H, Kuwert T, Gmeiner P (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". J. Med. Chem. 51 (6): 1800–10. doi:10.1021/jm701375u. PMID 18307287.
- Kulagowski JJ, Broughton HB, Curtis NR, et al. (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". J. Med. Chem. 39 (10): 1941–2. doi:10.1021/jm9600712. PMID 8642550.
- Patel S, Freedman S, Chapman KL, et al. (1 November 1997). "Biological profile of L-745,870, a selective antagonist with high affinity for the dopamine D4 receptor". J. Pharmacol. Exp. Ther. 283 (2): 636–47. PMID 9353380.
- Patel S, Patel S, Marwood R, et al. (December 1996). "Identification and pharmacological characterization of [125I]L-750,667, a novel radioligand for the dopamine D4 receptor". Mol. Pharmacol. 50 (6): 1658–64. PMID 8967990.
- 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 (1 October 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". J. Pharmacol. Exp. Ther. 287 (1): 167–86. PMID 9765336.
- Lanig H, Utz W, Gmeiner P (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". J. Med. Chem. 44 (8): 1151–7. doi:10.1021/jm001055e. PMID 11312915.
- "Dopamine Receptors: D4". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.
- Current Research on the DRD4 Gene
- 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.