Dopaminski receptor D₃

Dopaminski receptor D3
Dopaminski receptor D3
	Dopaminski D3 receptor sa etiklopridom (PDB 3PBL)
Dostupne strukture
	3PBL
Identifikatori
Simboli	DRD3; D3DR; ETM1; FET1
Vanjski ID	OMIM: 126451 MGI: 94925 HomoloGene: 623 IUPHAR: D3 GeneCards: DRD3 Gene
Ontologija gena
Molekularna funkcija	• aktivnost dopaminskog receptora, spregnutog sa Gi/Go; • aktivnost prenosnika signala; • receptorska aktivnost; • aktivnost G protein spregnutog receptora; • proteinsko vezivanje; • vezivanje leka; • vezivanje specifično za proteinski domen; • dopaminsko vezivanje;
Celularna komponenta	• membranska frakcija; • ćelijska membrana; • integralno sa ćelijskom membranom; • endocitna vezikula; • ćelijska projekcija; • apični deo ćelije;
Biološki proces	• negativna regulacija transkripcije od promotera RNK polimeraze II; • sinaptička transmisija, dopaminergička; • response na amfetamin; • regulacija krvne zapremine putem renin-angiotenzina; • internalizacija G protein spregnutog receptora; • ćelijska homeostaza jona kalcijuma; • signalni put G-protein spregnutog receptora; • aktivacija aktivnosti adenilat ciklaze signalnim putem dopaminskog receptora; • negativna regulacija aktivnosti adenilat ciklaze;
Pregled RNK izražavanja
	podaci
Ortolozi
Vrsta	Čovek
Entrez	1814
Ensembl	ENSG00000151577
UniProt	P35462
RefSeq (mRNA)	NM_000796.3
RefSeq (protein)	NP_000787.2
Lokacija (UCSC)	Chr 3:; 113.85 - 113.92 Mb
PubMed pretraga	[1]

D₃ dopaminski receptor je protein koji je kod ljudi kodiran DRD3 genom.^[1]^[2]

D₃ podtip dopaminskog receptora inhibira adenilil ciklazu putem inhibicije G proteina. Ovaj receptor je izražen u filogenetički starijim regionima mozga, što sugeriše da on ima ulogu u kognitivnim i emocionim funkcijama. On je meta za lekove kojima se tretira šizofrenija, addikcija, i Parkinsonova bolest^[3] . Alternativno splajsovanje ovog gena proizvodi višestruke transkriptne varijante koje mogu da koriraju različite izoforme, mada neke varijante mogu da budu bez funkcije.^[2]

D₃ agonisti poput 7-OH-DPAT, pramipeksola, i rotigotina, pokazuju antidepresantne efekte u modelima na glodarima za depresiju.^[4]^[5]

Ligandi

Brojni neselektivni lekovi na recept se vezuju za D₃ receptor. Među njima su neki od novijih dopaminskih agonista koji se koriste za lečenje Parkinsonove bolesti, npr. pramipeksol i ropinirol, koji se takođe vezuju za D₂ i nemaju jaku selektivnost.

Agonisti

8-OH-PBZI (cis-8-Hidroksi-3-(n-propil)-1,2,3a,4,5,9b-heksahidro-1H-benz[e]indol)
PF-219,061 ((R)-3-(4-Propilmorfolin-2-il)fenol): >1000-puta funkcionalna (efikasnost) selektivnost u odnosu na D₂^[6]
jedinjenje R,R-16: 250x selektivnost vezivanja u odnosu na D₂^[7]
trans-N4-[4-(2,3-Dihlorofenil)-1-piperazinil]cikloheksil3-metoksibenzamid, pun agonist, > 200-puta selektivniji u odnosu na D₄, D₂, 5-HT_1A, i α1-receptore^[8]
(-)-7[2-(4-Fenilpiperazin-1-il)etil]propilamino5,6,7,8-tetrahidronaftalen-2-ol^[9]
BP-897: parcijalni agonist^[10]
FAUC 73
FAUC 460: parcijalni agonist, dobar afinitet i selektivnost^[11]
FAUC 346: parcijalni agonist, podtip selektivan^[12]
PD-128,907
jedinjenje 12: parcijalni agonist, K_i = 0.41nM, 800x selektivnost vezivanja u odnosu na D₂^[13]
piribedil^[14]

Antagonisti

N-(4-(4-(2,3-Dihloro- ili 2-metoksifenil)piperazin-1-il)butil)heterobiarilkarboksamidi^[15]
FAUC 365, podtip selektivni antagonist^[12]
jedinjenje 29^[16]
Nafadotrid
NGB-2904^[17]
SB-277011-A, selektivni D₃ antagonist, 80x selektivniji u odnosu na D₂ bez parcijalnog agonističkog dejstva. Koristi se u ispitivanjima za adikcije
Domperidon - D₂ i D₃ antagonist

Chemical structures of selective D₃ receptor ligands.

Interakcije

Dopaminski receptor D3 formira interakcije sa CLIC6^[18] i EPB41L1.^[19]

Vidi još

Dopaminski receptor

Reference

^ Le Coniat M, Sokoloff P, Hillion J, Martres MP, Giros B, Pilon C, Schwartz JC, Berger R (1991). „Chromosomal localization of the human D3 dopamine receptor gene”. Hum Genet. 87 (5): 618—20. PMID 1916765.
^ ^а ^б „Entrez Gene: DRD3 dopamine receptor D3”.
^ Joyce, JN; Millan, MJ (2007). „Dopamine D3 receptor agonists for protection and repair in Parkinson's disease.”. Current opinion in pharmacology. 7 (1): 100—5. PMID 17174156.
^ Breuer ME; Groenink L; Oosting RS (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. PMID 19549514. doi:10.1016/j.ejphar.2009.06.029.
^ Bertaina-Anglade V, La Rochelle CD, Scheller DK (2006). „Antidepressant properties of rotigotine in experimental models of depression”. European Journal of Pharmacology. 548 (1-3): 106—14. PMID 16959244. doi:10.1016/j.ejphar.2006.07.022.
^ 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. PMID 17976986. doi:10.1016/j.bmcl.2007.10.059.
^ Peglion JL, Poitevin C, La Cour CM, 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. PMID 19324548. doi:10.1016/j.bmcl.2009.03.015.
^ 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. PMID 16451749. doi:10.1211/jpp.58.2.0008.
^ 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]propylamino5,6,7,8-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. PMID 18072730. doi:10.1021/jm070860r.
^ Spiller K, Xi ZX, Peng XQ, Newman AH, Ashby CR, Heidbreder C, Gaál J, Gardner EL (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. PMID 17985117. doi:10.1007/s00213-007-0986-6.
^ 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. PMID 18834111. doi:10.1021/jm800895v.
^ ^а ^б 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. PMID 12361386. doi:10.1021/jm025558r.
^ Chen J; Collins GT; Zhang J (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. PMC 2662387  . PMID 18785726. doi:10.1021/jm800471h.
^ Cagnotto A, Parotti L, Mennini T (1996). „In vitro affinity of piribedil for dopamine D3 receptor subtypes, an autoradiographic study”. Eur. J. Pharmacol. 313 (1-2): 63—7. PMID 8905329. doi:10.1016/0014-2999(96)00503-1.
^ Newman AH; Grundt P; Cyriac G (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. PMC 2760932  . PMID 19331412. doi:10.1021/jm900095y.
^ {{cite journal |author1=Grundt P |author2=Carlson EE |author3=Cao J |display-editors=etal |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=J. Med. Chem. |volume=48 |issue=3 |pages=839–48 |year=2005 |pmid=15689168 |doi=10.1021/jm049465g |url=}}
^ 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. PMID 17627675. doi:10.1111/j.1527-3458.2007.00013.x.
^ Griffon, Nathalie; Jeanneteau Freddy (2003). „CLIC6, a member of the intracellular chloride channel family, interacts with dopamine D(2)-like receptors”. Brain Res. Mol. Brain Res. Netherlands. 117 (1): 47—57. ISSN 0169-328X. PMID 14499480. doi:10.1016/S0169-328X(03)00283-3.
^ Binda, Alicia V; Kabbani Nadine (2002). „D2 and D3 dopamine receptor cell surface localization mediated by interaction with protein 4.1N”. Mol. Pharmacol. United States. 62 (3): 507—13. ISSN 0026-895X. PMID 12181426. doi:10.1124/mol.62.3.507.

Literatura

Missale C; Nash SR; Robinson SW (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. PMID 10978845. doi:10.1016/S0736-5748(00)00033-2.
Sokoloff P; Giros B; Martres MP (1990). „Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics.”. Nature. 347 (6289): 146—51. PMID 1975644. doi:10.1038/347146a0.
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. PMC 47477  . PMID 8415635. doi:10.1073/pnas.90.19.8942.
Griffon N; Crocq MA; Pilon C (1996). „Dopamine D3 receptor gene: organization, transcript variants, and polymorphism associated with schizophrenia.”. Am. J. Med. Genet. 67 (1): 63—70. PMID 8678117. doi:10.1002/(SICI)1096-8628(19960216)67:1<63::AID-AJMG11>3.0.CO;2-N.
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 (1997). „Further evidence of no association between Ser9Gly polymorphism of dopamine D3 receptor gene and schizophrenia.”. Am. J. Med. Genet. 74 (1): 40—3. PMID 9034004. doi:10.1002/(SICI)1096-8628(19970221)74:1<40::AID-AJMG9>3.0.CO;2-Z.
Gulcher JR; Jónsson P; Kong A (1997). „Mapping of a familial essential tremor gene, FET1, to chromosome 3q13.”. Nat. Genet. 17 (1): 84—7. PMID 9288103. doi:10.1038/ng0997-84.
Oldenhof J; Vickery R; Anafi M (1998). „SH3 binding domains in the dopamine D4 receptor.”. Biochemistry. 37 (45): 15726—36. PMID 9843378. doi:10.1021/bi981634.
Cargill M; Altshuler D; Ireland J (1999). „Characterization of single-nucleotide polymorphisms in coding regions of human genes.”. Nat. Genet. 22 (3): 231—8. PMID 10391209. doi:10.1038/10290.
Pilla M; Perachon S; Sautel F (1999). „Selective inhibition of cocaine-seeking behaviour by a partial dopamine D3 receptor agonist.”. Nature. 400 (6742): 371—5. PMID 10432116. doi:10.1038/22560.
Ilani T; Ben-Shachar D; Strous RD (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. PMC 14638  . PMID 11149951. doi:10.1073/pnas.021535398.
Lin R; Karpa K; Kabbani N (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. PMC 33197  . PMID 11320256. doi:10.1073/pnas.011538198.
Oldenhof J, Ray A, Vickery R, Van Tol HH (2001). „SH3 ligands in the dopamine D3 receptor.”. Cell. Signal. 13 (6): 411—6. PMID 11384839. doi:10.1016/S0898-6568(01)00157-7.
Soma M; Nakayama K; Rahmutula D (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.

Spoljašnje veze

„Dopamine Receptors: D₃”. IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.
Receptors,+Dopamine+D3 на US National Library of Medicine Medical Subject Headings (MeSH)

[pmid1916765-1] Le Coniat M, Sokoloff P, Hillion J, Martres MP, Giros B, Pilon C, Schwartz JC, Berger R (1991). „Chromosomal localization of the human D3 dopamine receptor gene”. Hum Genet. 87 (5): 618—20. PMID 1916765.

[entrez-2] а ^б „Entrez Gene: DRD3 dopamine receptor D3”.

[3] Joyce, JN; Millan, MJ (2007). „Dopamine D3 receptor agonists for protection and repair in Parkinson's disease.”. Current opinion in pharmacology. 7 (1): 100—5. PMID 17174156.

[pmid19549514-4] Breuer ME; Groenink L; Oosting RS (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. PMID 19549514. doi:10.1016/j.ejphar.2009.06.029.

[pmid16959244-5] Bertaina-Anglade V, La Rochelle CD, Scheller DK (2006). „Antidepressant properties of rotigotine in experimental models of depression”. European Journal of Pharmacology. 548 (1-3): 106—14. PMID 16959244. doi:10.1016/j.ejphar.2006.07.022.

[pmid17976986-6] 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. PMID 17976986. doi:10.1016/j.bmcl.2007.10.059.

[pmid19324548-7] Peglion JL, Poitevin C, La Cour CM, 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. PMID 19324548. doi:10.1016/j.bmcl.2009.03.015.

[pmid16451749-8] 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. PMID 16451749. doi:10.1211/jpp.58.2.0008.

[pmid18072730-9] 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]propylamino5,6,7,8-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. PMID 18072730. doi:10.1021/jm070860r.

[pmid17985117-10] Spiller K, Xi ZX, Peng XQ, Newman AH, Ashby CR, Heidbreder C, Gaál J, Gardner EL (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. PMID 17985117. doi:10.1007/s00213-007-0986-6.

[pmid18834111-11] 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. PMID 18834111. doi:10.1021/jm800895v.

[pmid12361386-12] а ^б 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. PMID 12361386. doi:10.1021/jm025558r.

[pmid18785726-13] Chen J; Collins GT; Zhang J (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. PMC 2662387  . PMID 18785726. doi:10.1021/jm800471h.

[pmid8905329-14] Cagnotto A, Parotti L, Mennini T (1996). „In vitro affinity of piribedil for dopamine D3 receptor subtypes, an autoradiographic study”. Eur. J. Pharmacol. 313 (1-2): 63—7. PMID 8905329. doi:10.1016/0014-2999(96)00503-1.

[pmid19331412-15] Newman AH; Grundt P; Cyriac G (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. PMC 2760932  . PMID 19331412. doi:10.1021/jm900095y.

[pmid15689168-16] {{cite journal |author1=Grundt P |author2=Carlson EE |author3=Cao J |display-editors=etal |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=J. Med. Chem. |volume=48 |issue=3 |pages=839–48 |year=2005 |pmid=15689168 |doi=10.1021/jm049465g |url=}}

[pmid17627675-17] 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. PMID 17627675. doi:10.1111/j.1527-3458.2007.00013.x.

[pmid14499480-18] Griffon, Nathalie; Jeanneteau Freddy (2003). „CLIC6, a member of the intracellular chloride channel family, interacts with dopamine D(2)-like receptors”. Brain Res. Mol. Brain Res. Netherlands. 117 (1): 47—57. ISSN 0169-328X. PMID 14499480. doi:10.1016/S0169-328X(03)00283-3.

[pmid12181426-19] Binda, Alicia V; Kabbani Nadine (2002). „D2 and D3 dopamine receptor cell surface localization mediated by interaction with protein 4.1N”. Mol. Pharmacol. United States. 62 (3): 507—13. ISSN 0026-895X. PMID 12181426. doi:10.1124/mol.62.3.507.

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