Biology:Dopamine receptor D3
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Short description: Subtype of Dopamine Receptor
 Generic protein structure example |
Dopamine receptor D3 is a protein that in humans is encoded by the DRD3 gene.[1][2]
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.[citation needed] It is a target for drugs which treat schizophrenia, drug addiction, and Parkinson's disease.[3] 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).[2]
Function
Alpha-synuclein (α-Syn) aggregation via Lewy bodies inclusion, a pathogenic signature exclusively present in PD patients, is decreased by D3 agonists while DA content is elevated by inhibiting DA reuptake and breakdown. The regulation of α-Syn aggregation and clearance enhances brain-derived neurotrophic factor (BDNF) secretion, which ultimately ameliorates neuroinflammation and oxidative stress while promoting neurogenesis and interacting with other DA receptors.[4][5]
D3 agonists like 7-OH-DPAT, pramipexole, and rotigotine, among others, display antidepressant effects in rodent models of depression.[6][7] Apomorphine has the ability to help PD patients with their cognition awareness.[8] In addition to having antidepressant properties such as regulating the depression-like behaviors and depression development, pramipexole has the capability to prevent and slow down cell apoptosis as well as to restore damaged neural networks and connections while rotigotine help PD patients to attenuates hyperpyrexia syndrome and schizophrenia.[9][10]
Animal studies
D3 agonists have been shown to disrupt prepulse inhibition of startle (PPI), a cross-species measure that recapitulates deficits in sensorimotor gating in neuropsychiatric disorders such as schizophrenia.[11][12][13] In contrast, D3-preferring antagonists have antipsychotic-like profiles in measures of PPI in rats.[14]
Ligands
Agonists
- trans-N-{4-[4-(2,3-Dichlorophenyl)-1-piperazinyl]cyclohexyl}-3-methoxybenzamide, full agonist, > 200-fold binding selectivity over D4, D2, 5-HT1A, and α1-receptors[15]
- (-)-7-{[2-(4-Phenylpiperazin-1-yl)ethyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-ol[16]
- 5-OH-DPAT
- 7-OH-DPAT
- Pergolide[17]
- 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[18]
- compound R,R-16: 250x binding selectivity over D2[19]
- Dopamine (endogenous agonist)
- ES609
- FAUC 54
- FAUC 73
- PD-128,907
- PF-219,061 (extremely selective) [20]
- PF-592,379[21]
- Piribedil[22] (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[23]
- Brexpiprazole (non-selective)
- Buspirone (non-selective)
- Cariprazine
- CJB 090
- CJ-1037 (extremely selective) [24]
- FAUC 460 (highly selective) [25]
- FAUC 346 (highly selective)[26]
- 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)
- Buspirone
- Cyproheptadine (non-selective)
- PG 01037 [27][28]
- Domperidone (peripheral D2 and D3 antagonist)
- FAUC 365, silent antagonist, subtype selective[26]
- GR-103,691
- GSK598809 (highly selective)
- Haloperidol (non-selective, blocks all dopamine receptor subtypes, though D3 with the strongest affinity)
- N-(4-(4-(2,3-Dichloro- or 2-methoxyphenyl)piperazin-1-yl)butyl)heterobiarylcarboxamides[29]
- Nafadotride
- NGB-2904[30]
- 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[31] and EPB41L1.[32]
DRD3 Ser9Gly polymorphism(rs6280), which is a single nucleotide polymorphism (SNP) with variant base C/T is linked to variation in PD such as depression severity, impulse control disorders, behavioral addiction and aberrant decision-making.[33][34][35][36]
See also
References
- ↑ "Chromosomal localization of the human D3 dopamine receptor gene". Human Genetics 87 (5): 618–620. September 1991. doi:10.1007/bf00209024. PMID 1916765.
- ↑ 2.0 2.1 "Entrez Gene: DRD3 dopamine receptor D3". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1814.
- ↑ "Dopamine D3 receptor agonists for protection and repair in Parkinson's disease". Current Opinion in Pharmacology 7 (1): 100–105. February 2007. doi:10.1016/j.coph.2006.11.004. PMID 17174156.
- ↑ "Dopamine D3 Receptors: A Potential Target to Treat Motivational Deficits in Parkinson’s Disease". Current Topics in Behavioral Neurosciences. 60. Berlin, Heidelberg: Springer Berlin Heidelberg. 2022. pp. 109–132. doi:10.1007/7854_2022_316. ISBN 978-3-031-23057-8.
- ↑ "Dopamine D3 receptor: A neglected participant in Parkinson Disease pathogenesis and treatment?". Ageing Research Reviews 57: 100994. January 2020. doi:10.1016/j.arr.2019.100994. PMID 31765822.
- ↑ "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): 134–140. August 2009. doi:10.1016/j.ejphar.2009.06.029. PMID 19549514.
- ↑ "Antidepressant properties of rotigotine in experimental models of depression". European Journal of Pharmacology 548 (1–3): 106–114. October 2006. doi:10.1016/j.ejphar.2006.07.022. PMID 16959244.
- ↑ "Loss of Awareness after Continuous Apomorphine Infusion Withdrawal in Parkinson's Disease". The Canadian Journal of Neurological Sciences. Le Journal Canadien des Sciences Neurologiques 47 (4): 576–577. July 2020. doi:10.1017/cjn.2020.43. PMID 32122433.
- ↑ "Pramipexole Inhibits Neuronal Apoptosis in Rats with Parkinson's Disease". Journal of Healthcare Engineering 2022: 7002630. 2022. doi:10.1155/2022/7002630. PMID 35463692.
- ↑ "An unwell patient with Parkinson's disease: Hyperpyrexia syndrome in a heatwave". JRSM Open 13 (8): 20542704221086162. August 2022. doi:10.1177/20542704221086162. PMID 35965941.
- ↑ "Heritable strain differences in sensitivity to the startle gating-disruptive effects of D2 but not D3 receptor stimulation". Behavioural Pharmacology 19 (8): 786–795. December 2008. doi:10.1097/FBP.0b013e32831c3b2b. PMID 19020413.
- ↑ "Parametric approaches towards understanding the effects of the preferential D3 receptor agonist pramipexole on prepulse inhibition in rats". Pharmacology, Biochemistry, and Behavior 95 (4): 473–478. June 2010. doi:10.1016/j.pbb.2010.04.001. PMID 20385162.
- ↑ "Stereochemical and neuroanatomical selectivity of pramipexole effects on sensorimotor gating in rats". Brain Research 1437: 69–76. February 2012. doi:10.1016/j.brainres.2011.12.007. PMID 22227455.
- ↑ "Using prepulse inhibition to detect functional D3 receptor antagonism: effects of WC10 and WC44". Pharmacology, Biochemistry, and Behavior 93 (2): 141–147. August 2009. doi:10.1016/j.pbb.2009.04.022. PMID 19426754.
- ↑ "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". The Journal of Pharmacy and Pharmacology 58 (2): 209–218. February 2006. doi:10.1211/jpp.58.2.0008. PMID 16451749.
- ↑ "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". Journal of Medicinal Chemistry 51 (1): 101–117. January 2008. doi:10.1021/jm070860r. PMID 18072730.
- ↑ "Functional potencies of new antiparkinsonian drugs at recombinant human dopamine D1, D2 and D3 receptors". European Journal of Pharmacology 366 (2–3): 293–300. February 1999. doi:10.1016/S0014-2999(98)00896-6. PMID 10082211.
- ↑ "CJ-1639: A Potent and Highly Selective Dopamine D3 Receptor Full Agonist". ACS Medicinal Chemistry Letters 2 (8): 620–625. August 2011. doi:10.1021/ml200100t. PMID 22125662.
- ↑ "Modulations of the amide function of the preferential dopamine D3 agonist (R,R)-S32504: improvements of affinity and selectivity for D3 versus D2 receptors". Bioorganic & Medicinal Chemistry Letters 19 (8): 2133–2138. April 2009. doi:10.1016/j.bmcl.2009.03.015. PMID 19324548.
- ↑ "Design and synthesis of a functionally selective D3 agonist and its in vivo delivery via the intranasal route". Bioorganic & Medicinal Chemistry Letters 17 (24): 6691–6696. December 2007. doi:10.1016/j.bmcl.2007.10.059. PMID 17976986.
- ↑ "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. June 2012. doi:10.1097/FBP.0b013e3283536d21. PMID 22470105.
- ↑ "In vitro affinity of piribedil for dopamine D3 receptor subtypes, an autoradiographic study". European Journal of Pharmacology 313 (1–2): 63–67. October 1996. doi:10.1016/0014-2999(96)00503-1. PMID 8905329.
- ↑ "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): 533–542. March 2008. doi:10.1007/s00213-007-0986-6. PMID 17985117.
- ↑ "Design, synthesis, and evaluation of potent and selective ligands for the dopamine 3 (D3) receptor with a novel in vivo behavioral profile". Journal of Medicinal Chemistry 51 (19): 5905–5908. October 2008. doi:10.1021/jm800471h. PMID 18785726.
- ↑ "Novel D3 selective dopaminergics incorporating enyne units as nonaromatic catechol bioisosteres: synthesis, bioactivity, and mutagenesis studies". Journal of Medicinal Chemistry 51 (21): 6829–6838. November 2008. doi:10.1021/jm800895v. PMID 18834111.
- ↑ 26.0 26.1 "Interactive SAR studies: rational discovery of super-potent and highly selective dopamine D3 receptor antagonists and partial agonists". Journal of Medicinal Chemistry 45 (21): 4594–4597. October 2002. doi:10.1021/jm025558r. PMID 12361386.
- ↑ {{cite journal | vauthors = Grundt P, Carlson EE, Cao J, Bennett CJ, McElveen E, Taylor M, Luedtke RR, Newman AH | display-authors = 6 | title = 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 | journal = Journal of Medicinal Chemistry | volume = 48 | issue = 3 | pages = 839–848 | date = February 2005 | pmid = 15689168 | doi = 10.1021/jm049465g }}
- ↑ "Characterization of the transport, metabolism, and pharmacokinetics of the dopamine D3 receptor-selective fluorenyl- and 2-pyridylphenyl amides developed for treatment of psychostimulant abuse". The Journal of Pharmacology and Experimental Therapeutics 333 (3): 854–864. June 2010. doi:10.1124/jpet.109.165084. PMID 20228156.
- ↑ "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". Journal of Medicinal Chemistry 52 (8): 2559–2570. April 2009. doi:10.1021/jm900095y. PMID 19331412.
- ↑ "Pharmacological actions of NGB 2904, a selective dopamine D3 receptor antagonist, in animal models of drug addiction". CNS Drug Reviews 13 (2): 240–259. 2007. doi:10.1111/j.1527-3458.2007.00013.x. PMID 17627675.
- ↑ "CLIC6, a member of the intracellular chloride channel family, interacts with dopamine D(2)-like receptors". Brain Research. Molecular Brain Research 117 (1): 47–57. September 2003. doi:10.1016/S0169-328X(03)00283-3. PMID 14499480.
- ↑ "D2 and D3 dopamine receptor cell surface localization mediated by interaction with protein 4.1N". Molecular Pharmacology 62 (3): 507–513. September 2002. doi:10.1124/mol.62.3.507. PMID 12181426.
- ↑ "Dopamine D3 receptor Ser9Gly variant is associated with impulse control disorders in Parkinson's disease patients". Parkinsonism & Related Disorders 30: 13–17. September 2016. doi:10.1016/j.parkreldis.2016.06.005. PMID 27325396.
- ↑ "The Association between DRD3 Ser9Gly Polymorphism and Depression Severity in Parkinson's Disease". Parkinson's Disease 2019: 1642087. 2019-04-15. doi:10.1155/2019/1642087. PMID 31143436.
- ↑ "Behavioral addictions in early-onset Parkinson disease are associated with DRD3 variants". Parkinsonism & Related Disorders 49: 100–103. April 2018. doi:10.1016/j.parkreldis.2018.01.010. PMID 29361389.
- ↑ "Dopamine Receptor D3 rs6280 is Associated with Aberrant Decision-Making in Parkinson's Disease". Movement Disorders Clinical Practice 5 (4): 413–416. 2018. doi:10.1002/mdc3.12631. PMID 30363458.
Further reading
- "Dopamine receptors: from structure to function". Physiological Reviews 78 (1): 189–225. January 1998. doi:10.1152/physrev.1998.78.1.189. PMID 9457173.
- "Coupling of dopamine receptor subtypes to multiple and diverse G proteins". International Journal of Developmental Neuroscience 18 (7): 669–677. November 2000. doi:10.1016/S0736-5748(00)00033-2. PMID 10978845.
- "Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics". Nature 347 (6289): 146–151. September 1990. doi:10.1038/347146a0. PMID 1975644. Bibcode: 1990Natur.347..146S.
- "[Gene cloning of human dopaminergic D3 receptor and identification of its chromosome]". Comptes Rendus de l'Académie des Sciences, Série III 311 (13): 501–508. 1991. PMID 2129115.
- "On the origin of mRNA encoding the truncated dopamine D3-type receptor D3nf and detection of D3nf-like immunoreactivity in human brain". The Journal of Biological Chemistry 269 (46): 29220–29226. November 1994. doi:10.1016/S0021-9258(19)62033-8. PMID 7961889.
- "Selective loss of dopamine D3-type receptor mRNA expression in parietal and motor cortices of patients with chronic schizophrenia". Proceedings of the National Academy of Sciences of the United States of America 90 (19): 8942–8946. October 1993. doi:10.1073/pnas.90.19.8942. PMID 8415635. Bibcode: 1993PNAS...90.8942S.
- "Dopamine D3 receptor gene: organization, transcript variants, and polymorphism associated with schizophrenia". American Journal of Medical Genetics 67 (1): 63–70. February 1996. doi:10.1002/(SICI)1096-8628(19960216)67:1<63::AID-AJMG11>3.0.CO;2-N. PMID 8678117.
- "Adaptive increase in D3 dopamine receptors in the brain reward circuits of human cocaine fatalities". The Journal of Neuroscience 16 (19): 6100–6106. October 1996. doi:10.1523/JNEUROSCI.16-19-06100.1996. PMID 8815892.
- "Further evidence of no association between Ser9Gly polymorphism of dopamine D3 receptor gene and schizophrenia". American Journal of Medical Genetics 74 (1): 40–43. February 1997. doi:10.1002/(SICI)1096-8628(19970221)74:1<40::AID-AJMG9>3.0.CO;2-Z. PMID 9034004. http://ntur.lib.ntu.edu.tw//handle/246246/105072.
- "Mapping of a familial essential tremor gene, FET1, to chromosome 3q13". Nature Genetics 17 (1): 84–87. September 1997. doi:10.1038/ng0997-84. PMID 9288103.
- "SH3 binding domains in the dopamine D4 receptor". Biochemistry 37 (45): 15726–15736. November 1998. doi:10.1021/bi981634+. PMID 9843378. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape9/PQDD_0017/NQ45764.pdf.
- "Characterization of single-nucleotide polymorphisms in coding regions of human genes". Nature Genetics 22 (3): 231–238. July 1999. doi:10.1038/10290. PMID 10391209.
- "Selective inhibition of cocaine-seeking behaviour by a partial dopamine D3 receptor agonist". Nature 400 (6742): 371–375. July 1999. doi:10.1038/22560. PMID 10432116. Bibcode: 1999Natur.400..371P.
- "A peripheral marker for schizophrenia: Increased levels of D3 dopamine receptor mRNA in blood lymphocytes". Proceedings of the National Academy of Sciences of the United States of America 98 (2): 625–628. January 2001. doi:10.1073/pnas.021535398. PMID 11149951.
- "Dopamine D2 and D3 receptors are linked to the actin cytoskeleton via interaction with filamin A". Proceedings of the National Academy of Sciences of the United States of America 98 (9): 5258–5263. April 2001. doi:10.1073/pnas.011538198. PMID 11320256. Bibcode: 2001PNAS...98.5258L.
- "SH3 ligands in the dopamine D3 receptor". Cellular Signalling 13 (6): 411–416. June 2001. doi:10.1016/S0898-6568(01)00157-7. PMID 11384839.
- "Ser9Gly polymorphism in the dopamine D3 receptor gene is not associated with essential hypertension in the Japanese". Medical Science Monitor 8 (1): CR1–CR4. January 2002. PMID 11796958.
External links
- "Dopamine Receptors: D3". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2256.
- 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.
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