Dopaminski receptor D₄

Dopaminski receptor D4
Dopaminski receptor D4
Identifikatori
Simboli	DRD4; D4DR
Vanjski ID	OMIM: 126452 MGI: 94926 HomoloGene: 20215 IUPHAR: D4 GeneCards: DRD4 Gene
Ontologija gena
Molekularna funkcija	• aktivnost dopaminskog receptora, spregnutog sa Gi/Go; • aktivnost prenosa signala; • receptorska aktivnost; • aktivnost G-protein spregnutog receptora; • aktivnost dopaminskog receptora; • proteinsko vezivanje; • vezivanje lekova; • regulacija aktivnosti kalijumovog kanala; • vezivanje za SH3 domen; • dopaminsko vezivanje;
Celularna komponenta	• citoplazma; • ćelijska membrana; • integralno sa ćelijskom membranom; • ćelijski korteks; • vezikularna membrana; • membrana; • akson; • neuronsko ćelijsko telo;
Biološki proces	• aktivacija MAPK aktivnosti; • respons na strah; • dopaminergička sinaptička transmisija; • respons na amfetamin; • homeostaza ćelijskih jona kalcijuma; • negativna regulacija aktivnosti adenilat ciklaze; • inhibicija aktivnosti adenilat ciklaze signalnim putem dopaminskog receptora; • signalni put dopaminskog receptora; • kratkotrajna memorija; • lokomotorno ponašanje odraslih; • olfaktorno učenje;
Pregled RNK izražavanja
	podaci
Ortolozi
Vrsta	Čovek
Entrez	1815
Ensembl	ENSG00000069696
UniProt	P21917
RefSeq (mRNA)	NM_000797.3
RefSeq (protein)	NP_000788.2
Lokacija (UCSC)	Chr 11:; 0.64 - 0.64 Mb
PubMed pretraga	[1]

Dopaminski receptor D₄ je G protein spregnuti receptor kodiran DRD4 genom.^[1] Poput drugih dopaminskih receptora, D₄ receptor se aktivira neurotransmiterom dopaminom. On je povezan sa mnogim neurološkim i psihijatrijskim oboljenjima, neka od kojih su šizofrenija, Parkinsonova bolest, bipolarni poremećaj, adikcije, i poremećaji ishrane kao što su anoreksija nervoza, bulimija nervoza i nekontrolisano jedenje.

D4 je biološka meta za lekove kojima se tretira šizofrenija i Parkinsonova bolest. Ovaj receptor je sličan sa D₂ receptorom, u smislu da aktivirani receptor inhibira enzim adenilat cilazu, čime se redukuje intraćelijska koncentracija sekundarnog glasnika cikličnog AMP-a.^[2]

Ligandi

Hemijske strukture reprezentativnih D₄ liganda.

Agonisti

WAY-100635: potentan puni agonist, sa 5-HT_1A antagonistnom komponentom^[3]
A-412,997: pun agonist, > 100-puta selektivniji u odnosu na panel od sedamdeset različitih receptora i jonskih kanala^[4]
ABT-724 - razvijen za lečenje impotencije^[5]
ABT-670 - ima bolju oralnu biodostupnost od ABT-724^[6]
FAUC 316: parcijalni agonist, > 8600-puta selektivniji u odnosu na druge dopaminske receptore^[7]
FAUC 299: parcijalni agonist^[7]
(E)-1-aril-3-(4-piridinpiperazin-1-il)propanon oksimi^[8]
PIP3EA: parcijalni agonist^[9]
Flibanzerin - parcijalni agonist
PD-168,077 - D₄ selektivan, ali se isto tako vezuje za α1A, α2C i 5HT_1A
CP-226,269 - D₄ selektivan, ali se isto tako vezuje za D₂, D₃, α2A, α2C i 5HT_1A
Ro10-5824 - parcijalni agonist

Antagonisti

A-381393: potentan, podtip selektivan antagonist (>2700-puta)^[10]
FAUC 213^[11]
L-745,870^[12]^[13]
L-750,667^[14]
S 18126: takođe σ1 afin^[15]
Fananserin - mešoviti 5-HT_2A / D₄ antagonist

Inverzni agonisti

FAUC F41: inverzni agonist, podtip selektivan u odnosu na D₂ i D₃^[11]^[16]

Reference

^ Van Tol HH, Bunzow JR, Guan HC, Sunahara RK, Seeman P, Niznik HB, Civelli O (1991). „Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine”. Nature. 350 (6319): 610—4. PMID 1840645. doi:10.1038/350610a0.
^ Neve KA, Seamans JK, Trantham-Davidson H (2004). „Dopamine receptor signaling”. J. Recept. Signal Transduct. Res. 24 (3): 165—205. PMID 15521361. doi:10.1081/RRS-200029981.
^ 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. PMID 16915381. doi:10.1007/s00213-006-0490-4.
^ 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. PMID 16153699. doi:10.1016/j.pbb.2005.08.001.
^ 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 (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. PMID 15239663. doi:10.1021/jm030505a.
^ Patel MV; Kolasa T; Mortell K (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. PMID 17149874. doi:10.1021/jm060662k.
^ ^а ^б 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. PMID 11087581. doi:10.1021/jm0009989.
^ Kolasa T; Matulenko MA; Hakeem AA (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. PMID 16913699. doi:10.1021/jm060279f.
^ Enguehard-Gueiffier C; Hübner H; El Hakmaoui A (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. PMID 16789750. doi:10.1021/jm060166w.
^ Nakane M; Cowart MD; Hsieh GC (2005). „2-[4-(3,4-Dimethylphenyl)piperazin-1-ylmethyl]-1H benzoimidazole (A-381393), a selective dopamine D4 receptor antagonist”. Neuropharmacology. 49 (1): 112—21. PMID 15992586. doi:10.1016/j.neuropharm.2005.02.004.
^ ^а ^б 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. PMID 18307287. doi:10.1021/jm701375u.
^ Kulagowski JJ; Broughton HB; Curtis NR (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. PMID 8642550. doi:10.1021/jm9600712.
^ Patel S; Freedman S; Chapman KL (1. 11. 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 (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. ^{[мртва веза]}
^ 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. 10. 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. Архивирано из оригинала 12. 07. 2003. г. Приступљено 09. 04. 2012.
^ 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. PMID 11312915. doi:10.1021/jm001055e.

Spoljašnje veze

„Dopamine Receptors: D₄”. IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Архивирано из оригинала 05. 03. 2012. г.
Istraživanja DRD₄ gena
Receptors,+Dopamine+D4 на US National Library of Medicine Medical Subject Headings (MeSH)
Marisa Wilson. „Are you a thrill seeker??”. Davidson College. Приступљено 05. 04. 2008.
„The D4DR Gene”. D4DR Club. Архивирано из оригинала 30. 04. 2008. г. Приступљено 05. 04. 2008.

Vidi još

Dopaminski receptor

[pmid1840645-1] Van Tol HH, Bunzow JR, Guan HC, Sunahara RK, Seeman P, Niznik HB, Civelli O (1991). „Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine”. Nature. 350 (6319): 610—4. PMID 1840645. doi:10.1038/350610a0.

[pmid15521361-2] Neve KA, Seamans JK, Trantham-Davidson H (2004). „Dopamine receptor signaling”. J. Recept. Signal Transduct. Res. 24 (3): 165—205. PMID 15521361. doi:10.1081/RRS-200029981.

[pmid16915381-3] 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. PMID 16915381. doi:10.1007/s00213-006-0490-4.

[pmid16153699-4] 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. PMID 16153699. doi:10.1016/j.pbb.2005.08.001.

[pmid15239663-5] 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 (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. PMID 15239663. doi:10.1021/jm030505a.

[6] Patel MV; Kolasa T; Mortell K (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. PMID 17149874. doi:10.1021/jm060662k.

[pmid11087581-7] а ^б 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. PMID 11087581. doi:10.1021/jm0009989.

[8] Kolasa T; Matulenko MA; Hakeem AA (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. PMID 16913699. doi:10.1021/jm060279f.

[9] Enguehard-Gueiffier C; Hübner H; El Hakmaoui A (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. PMID 16789750. doi:10.1021/jm060166w.

[10] Nakane M; Cowart MD; Hsieh GC (2005). „2-[4-(3,4-Dimethylphenyl)piperazin-1-ylmethyl]-1H benzoimidazole (A-381393), a selective dopamine D4 receptor antagonist”. Neuropharmacology. 49 (1): 112—21. PMID 15992586. doi:10.1016/j.neuropharm.2005.02.004.

[pmid18307287-11] а ^б 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. PMID 18307287. doi:10.1021/jm701375u.

[12] Kulagowski JJ; Broughton HB; Curtis NR (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. PMID 8642550. doi:10.1021/jm9600712.

[13] Patel S; Freedman S; Chapman KL (1. 11. 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.

[14] Patel S; Patel S; Marwood R (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. ^{[мртва веза]}

[pmid9765336-15] 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. 10. 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. Архивирано из оригинала 12. 07. 2003. г. Приступљено 09. 04. 2012.

[pmid11312915-16] 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. PMID 11312915. doi:10.1021/jm001055e.

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Dopaminski receptor D4