Dopaminski receptor D4

Из Википедије, слободне енциклопедије
Dopaminski receptor D4
Identifikatori
Simboli DRD4; D4DR
Vanjski ID OMIM126452 MGI94926 HomoloGene20215 IUPHAR: D4 GeneCards: DRD4 Gene
Pregled RNK izražavanja
PBB GE DRD4 208215 x at tn.png
podaci
Ortolozi
Vrsta Čovek Miš
Entrez 1815 13491
Ensembl ENSG00000069696 ENSMUSG00000025496
UniProt P21917 P51436
RefSeq (mRNA) NM_000797.3 NM_007878.2
RefSeq (protein) NP_000788.2 NP_031904.1
Lokacija (UCSC) Chr 11:
0.64 - 0.64 Mb
Chr 7:
148.48 - 148.48 Mb
PubMed pretraga [1] [2]

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[уреди]

Hemijske strukture reprezentativnih D4 liganda.

Agonisti[уреди]

  • WAY-100635: potentan puni agonist, sa 5-HT1A 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 5HT1A
  • CP-226,269 - D4 selektivan, ali se isto tako vezuje za D2, D3, α2A, α2C i 5HT1A
  • Ro10-5824 - parcijalni agonist

Antagonisti[уреди]

Inverzni agonisti[уреди]

Reference[уреди]

  1. ^ 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. 
  2. ^ 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. 
  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. DOI:10.1007/s00213-006-0490-4. PMID 16915381. 
  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. DOI:10.1016/j.pbb.2005.08.001. PMID 16153699. 
  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 (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. 
  6. ^ 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. 
  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. DOI:10.1021/jm0009989. PMID 11087581. 
  8. ^ 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. 
  9. ^ 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. 
  10. ^ 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. 
  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. DOI:10.1021/jm701375u. PMID 18307287. 
  12. ^ 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. 
  13. ^ 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. 
  14. ^ 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. 
  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. 
  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. DOI:10.1021/jm001055e. PMID 11312915. 

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