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D4 receptor

Family: Dopamine receptors

Contents:
Gene and Protein Information
Previous and Unofficial Names
Database Links
Agonists
Antagonists
Transduction Mechanisms
Tissue Distribution
Expression Datasets
Functional Assays
Physiological Functions
Physiological Consequences of Altering Gene Expression
Phenotypes, Alleles and Disease Models
Biologically Significant Variants
General Comments
References
Gene and Protein Information
class A G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 467 11p15.5 DRD4 dopamine receptor D4 48
Mouse 7 387 7 F5 Drd4 dopamine receptor D4 27
Rat 7 387 1q41 Drd4 dopamine receptor D4 9
Previous and Unofficial Names
dopamine D4 receptor
D4RA
D(4) dopamine receptor
Dopamine receptor D4
d(2C) dopamine receptor
dopamine receptor 4
Drd-4
D4R
AW125663
Database Links
ChEMBL Target 90 (Hs), 10086 (Mm), 12173 (Rn)
DrugBank Target 432 (Hs)
Ensembl ENSG00000069696 (Hs), ENSMUSG00000025496 (Mm), ENSRNOG00000017927 (Rn)
Entrez Gene 1815 (Hs), 13491 (Mm), 25432 (Rn)
GeneCards DRD4 (Hs)
GenitoUrinary Development Molecular Anatomy Project Drd4 (Mm)
HomoloGene 20215 (Hs)
Human Protein Reference Database 00541 (Hs)
InterPro P21917 (Hs), P51436 (Mm), P30729 (Rn)
KEGG Gene hsa:1815 (Hs), mmu:13491 (Mm), rno:25432 (Rn)
OMIM 126452 (Hs)
PharmGKB Gene PA27480 (Hs)
PhosphoSitePlus P21917 (Hs), P51436 (Mm), P30729 (Rn)
Protein Ontology (PRO) PRO:000001179 (Hs)
RefSeq Nucleotide NM_000797 (Hs), NM_007878 (Mm), NM_012944 (Rn)
RefSeq Protein NP_000788 (Hs), NP_031904 (Mm), NP_037076 (Rn)
TreeFam ENSG00000069696 (Hs), ENSMUSG00000025496 (Mm), ENSRNOG00000017927 (Rn)
UniGene Hs. 99922 (Hs)
UniProt P21917 (Hs), P51436 (Mm), P30729 (Rn)
Wikipedia D4 receptor
Dopamine receptors
Search for 3D structures on the PDB
Search by keyword: Dopamine receptors D4 receptor Search by accession number: P30729, P21917, P51436
Natural/Endogenous Ligand(s)
dopamine
Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
CP-226269 Rn Partial agonist 9.4 pKi 15
FAUC213 Rn Partial agonist 9.0 pKi 15
PD168,077 Rn Partial agonist 8.8 pKi 15
apomorphine Hs Partial agonist 8.4 pKi 23
lisuride Hs Partial agonist 8.3 pKi 23
roxindole Hs Partial agonist 8.2 pKi 23
A412997 Rn Agonist 8.1 pKi 24
dopamine Hs Full agonist 7.6 pKi 48
quinpirole Hs Full agonist 7.5 pKi 23
dopamine Rn Full agonist 7.4 pKi 37
cabergoline Hs Partial agonist 7.3 pKi 23
pergolide Hs Partial agonist 7.2 pKi 23
SKF-82526 Hs Full agonist 6.5 pKi 48
View species-specific agonist tables
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
nemonapride Hs Antagonist 10.0 pKd 39
[125I]L750667 Hs Antagonist 9.8 pKd 29
[3H]spiperone Hs Antagonist 9.5 pKd 14
[3H]NGD941 Hs Antagonist 8.3 pKd 32
L-750,667 Rn Antagonist 10.0 pKi 37
RBI257 Rn Antagonist 9.6 pKi 15
CP-293019 Rn Antagonist 9.5 pKi 15
NGD 94-1 Rn Antagonist 9.5 pKi 15
[3H]N-methylspiperone Rn Antagonist 9.5 pKi 37
L745870 Hs Antagonist 9.4 pKi 16
spiperone Hs Antagonist 9.3 pKi 6
FAUC213 Rn Antagonist 9.0 pKi 15
U101958 Hs Antagonist 8.9 pKi 38
haloperidol Hs Antagonist 8.7 pKi 17
PNU101,387G Rn Antagonist 8.7 pKi 15
L741742 Hs Antagonist 8.5 pKi 35
terguride Hs Antagonist 8.1 pKi 23
chlorpromazine Hs Antagonist 7.8 pKi 17
Ro 10-4548 Rn Antagonist 7.8 pKi 15
clozapine Hs Antagonist 7.5 pKi 17
aripiprazole Rn Antagonist 7.3 pKi 37
eticlopride Hs Antagonist 7.0 pKi 6
piribedil Hs Antagonist 6.5 pKi 23
bromocriptine Hs Antagonist 6.4 pKi 23
nafadotride Rn Antagonist 6.4 pKi 37
(+)-butaclamol Hs Antagonist 6.3 pKi 29
raclopride Rn Antagonist 5.7 pKi 37
(-)-sulpiride Hs Antagonist 5.7 pKi 29
(+)-sulpiride Hs Antagonist 5.7 pKi 29
View species-specific antagonist tables

Explore drug-target interactions for this set of compounds using iPHACE

Primary Transduction Mechanisms
Transducer Effector/Response
Gi/Go family Adenylate cyclase inhibition
References:  30
Tissue Distribution
Brain: Occipital lobe, cerebellum, hippocampus, middle frontal gyrus of temporal lobe, middle frontal gyrus of frontal lobe, cingulate gyrus of frontal lobe, amygdala > superior temporal gyrus of temporal lobe, superior frontal gyrus of frontal lobe, thalamus, septal nuclei, hypothalamus > substantia nigra, caudate nucleus, globus pallidus, superior parietal lobe.
Species:  Human
Technique:  RT-PCR
References:  25
Brain: Pre-frontal cortex, temporal neocortex > occipital cortex.
Species:  Human
Technique:  in situ hybridization.
References:  21
Pulmonary artery.
Species:  Human
Technique:  Western Blot and Immunohistochemistry.
References:  33
Aortic endothelium, umbilical vein endothelium.
Species:  Human
Technique:  RT-PCR
References:  50
Retina, photoreceptor cell layer and inner nuclear and ganglion cell layers.
Species:  Mouse
Technique:  RT-PCR and in situ hybridization.
References:  4
Brain (especially cerebellum), eye, adrenal gland, testes, superior cervical ganglion, submaxillary gland, pancreas.
Species:  Mouse
Technique:  RT-PCR
References:  45
Striatum, substantia nigra pars reticulata, entopeduncular nucleus, globus pallidus.
Species:  Rat
Technique:  Immunohistochemistry.
References:  34
Kidney: Cortex > inner medulla.
Species:  Rat
Technique:  Western Blot and Immunocytochemistry.
References:  41
Nucleus accumbens shell.
Species:  Rat
Technique:  immunocytochemistry.
References:  46
Kidney: Cortical collecting duct.
Species:  Rat
Technique:  RT-PCR
References:  43
Expression Datasets

Click here to show/hide data

Log average relative transcript abundance in mouse tissues measured by qPCR from Regard, J.B., Sato, I.T., and Coughlin, S.R. (2008). Anatomical profiling of G protein-coupled receptor expression. Cell, 135(3): 561-71. [PMID:18984166] [Raw data: website]

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Functional Assays
Measurement of Cl- currents in Xenopus oocytes transfected with murine D2L and D2S receptors.
Species:  Mouse
Tissue:  Xenopus oocytes.
Response measured:  Stimulation of Cl- influx.
References:  42
Measurement of cAMP levels in HEK 293 cells transfected with the human D4 receptor.
Species:  Human
Tissue:  HEK 293 cells.
Response measured:  Inhibition of cAMP accumulation.
References:  2,10,20
Measurement of cAMP levels in CHO cells transfected with the human D4 receptor.
Species:  Human
Tissue:  CHO cells.
Response measured:  Inhibition of cAMP accumulation.
References:  1,3,18,28,40,47
Measurement of cAMP levels in COS-7 cells transfected with the human D4 receptor.
Species:  Human
Tissue:  COS-7 cells.
Response measured:  Inhibition of cAMP accumulation.
References:  1
Measurement of cAMP levels in Chinese hamster lung fibroblast CCL39 cells transfected with the rat D4 receptor.
Species:  Rat
Tissue:  Chinese hamster lung fibroblast CCL39 cells.
Response measured:  Inhibition of cAMP accumulation.
References:  12
Measurement of high-voltage Ca2+ current in cultured granule cells from neonatal rat cerebellum endogenously expressing the D4 receptor.
Species:  Rat
Tissue:  Granule cells.
Response measured:  Inhibition of L-type Ca2+ current.
References:  22
Measurement of mitogenesis in CHO cells transfected with the human D4 receptor.
Species:  Human
Tissue:  CHO cells.
Response measured:  Mitogenesis.
References:  38
Measurement of inwardly rectifying K+ currents in Xenopus oocytes transfected with the human D4 receptor.
Species:  Human
Tissue:  Xenopus oocytes.
Response measured:  Activation of GIRK1 channels.
References:  31
Physiological Functions
Modulation of the dark level of light-sensitive cAMP in photoreceptors.
Species:  Mouse
Tissue:  Retina.
References:  4
Regulation of electrolyte and water transport.
Species:  Rat
Tissue:  Kidney.
References:  41,43
Modulation of von Willebrand factor secretion in endothelial cells.
Species:  Human
Tissue:  Endothelium.
References:  50
Modulation of gastric acid secretion.
Species:  Rat
Tissue:  In vivo.
References:  13
Physiological Consequences of Altering Gene Expression
D4 receptor knockout mice exhibit an increased sensitivity to ethanol, cocaine and methamphetamine.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  36
D4 receptor knockout mice exhibit a decrease in novelty-related exploration.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  5
D4 receptor knockout mice exhibit increased avoidance behaviour to unconditioned stimuli.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  8
D4 receptor knockout mice exhibit dysfunctional light-evoked regulation of cAMP in photoreceptors and abnormal retinal adaptation.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  26
D4 knockout mice exhibit increased co-ordination.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  36
Phenotypes, Alleles and Disease Models Mouse data from MGI

Click here to show/hide data

Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Drd4tm1(IL2RA)Tao Drd4tm1(IL2RA)Tao/Drd4tm1(IL2RA)Tao
involves: C57BL/6J		 MGI:94926  MP:0003463 abnormal single cell response PMID: 14684868 
Drd4tm1Dkg Drd4tm1Dkg/Drd4tm1Dkg
involves: 129P2/OlaHsd * C57BL/6J		 MGI:94926  MP:0001417 decreased exploration in new environment PMID: 10531457 
Drd4tm1Dkg Drd4tm1Dkg/Drd4tm1Dkg
involves: 129P2/OlaHsd * C57BL/6J		 MGI:94926  MP:0002757 decreased vertical activity PMID: 9323127 
Drd4tm1Dkg Drd4tm1Dkg/Drd4tm1Dkg
involves: 129P2/OlaHsd * C57BL/6J		 MGI:94926  MP:0009754 enhanced behavioral response to cocaine PMID: 9323127 
Drd4tm1Dkg Drd4tm1Dkg/Drd4tm1Dkg
involves: 129P2/OlaHsd * C57BL/6J		 MGI:94926  MP:0003858 enhanced coordination PMID: 9323127 
Drd4tm1Dkg Drd4tm1Dkg/Drd4tm1Dkg
involves: 129P2/OlaHsd * C57BL/6J		 MGI:94926  MP:0002629 hyperactivity elicited by ethanol administration PMID: 9323127 
Drd4tm1Dkg Drd4tm1Dkg/Drd4tm1Dkg
involves: 129P2/OlaHsd * C57BL/6J		 MGI:94926  MP:0001402 hypoactivity PMID: 9323127 
Drd4tm1Dkg Drd4tm1Dkg/Drd4tm1Dkg
involves: 129P2/OlaHsd * C57BL/6J		 MGI:94926  MP:0009750 impaired behavioral response to addictive substance PMID: 9323127 
Drd4tm1Dkg Drd4tm1Dkg/Drd4tm1Dkg
involves: 129P2/OlaHsd * C57BL/6J		 MGI:94926  MP:0001906 increased dopamine level PMID: 9323127 
Biologically Significant Variants
DRD4 7-repeat allele may increase likelihood of ADHD.
Type:  Repeat polymorphism of Exon III
Species:  Human
References:  7,44
General Comments
Human and primate receptors have a variable number (2-10) of imperfect 48 bp repeats in exon 3 [19,49]. This leads to a highly variable length and aa composition of the putative third cytoplasmic loop, apparently not associated with any marked variation in pharmacology. Most D4 receptor-antagonists display agonistic activities in some heterologous expression systems [10-11].

REFERENCES

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1. Asghari, V., Sanyal, S., Buchwaldt, S., Paterson, A., Jovanovic, V. and Van Tol, H. H. (1995) Modulation of intracellular cyclic AMP levels by different human dopamine D4 receptor variants. J Neurochem, 65: 1157-1165. [PMID:7643093]

2. Chemel, B. R., Roth, B. L., Armbruster, B., Watts, V. J. and Nichols, D. E. (2006) WAY-100635 is a potent dopamine D4 receptor agonist. Psychopharmacology (Berl), 188: 244-251. [PMID:16915381]

3. Chio, C. L., Drong, R. F., Riley, D. T., Gill, G. S., Slighton, J. L. and Huff, R. M. (1994) D4 dopamine receptor-mediated signalling events determined in transfected Chinese hamster ovary cells. J. Biol. Chem., 269: 11813-11819. [PMID:7512953]

4. Cohen, A. I., Todd, R. D., Harmon, S. and O'Malley, K. L. (1992) Photoreceptors of mouse retinas possess D4 receptors coupled to adenylate cyclase. Proc Natl Acad Sci U S A, 89: 12093-12097. [PMID:1334557]

5. Dulawa, S. C., Grandy, D. K., Low, M. J., Paulus, M. P. and Geyer, M. A. (1999) Dopamine D4 receptor-knock-out mice exhibit reduced exploration of novel stimuli. J. Neurosci., 19: 9550-9556. [PMID:10531457]

6. Durcan, M. J., Rigdon, G. C., Norman, M. H. and Morgan, P. F. (1995) Is clozapine selective for the dopamine D4 receptor?. Life Sci, 57: PL275-PL283. [PMID:7475902]

7. El-Faddagh, M., Laucht, M., Maras, A., Vöhringer, L. and Schmidt, M. H. (2004) Association of dopamine D4 receptor (DRD4) gene with attention-deficit/hyperactivity disorder (ADHD) in a high-risk community sample: a longitudinal study from birth to 11 years of age. J Neural Transm, 111: 883-889. [PMID:15206004]

8. Falzone, T. L., Gelman, D. M., Young, J. I., Grandy, D. K., Low, M. J. and Rubinstein, M. (2002) Absence of dopamine D4 receptors results in enhanced reactivity to unconditioned, but not conditioned, fear. Eur J Neurosci, 15: 158-164. [PMID:11860516]

9. Fishburn, C. S., Carmon, S. and Fuchs, S. (1995) Molecular cloning and characterisation of the gene encoding the murine D4 dopamine receptor. FEBS Lett., 361: 215-219. [PMID:7698326]

10. Gazi, L., Bobirnac, I., Danzeisen, M., Schüpbach, E., Bruinvels, A. T., Geisse, S., Sommer, B., Hoyer, D., Tricklebank, M. and Schoeffter, P. (1998) The agonist activities of the putative antipsychotic agents, L-745,870 and U-101958 in HEK293 cells expressing the human dopamine D4.4 receptor. Br. J. Pharmacol., 124: 889-896. [PMID:9692773]

11. Gazi, L., Bobirnac, I., Danzeisen, M., Schüpbach, E., Langenegger, D., Sommer, B., Hoyer, D., Tricklebank, M. and Schoeffter, P. (1999) Receptor density as a factor governing the efficacy of the dopamine D4 receptor ligands, L-745,870 and U-101958 at human recombinant D4.4 receptors expressed in CHO cells. Br. J. Pharmacol., 128: 613-620. [PMID:10516640]

12. Gazi, L., Schoeffter, P., Nunn, C., Croskery, K., Hoyer, D. and Feuerbach, D. (2000) Cloning, expression, functional coupling and pharmacological characterization of the rat dopamine D4 receptor. Naunyn Schmiedebergs Arch Pharmacol, 361: 555-564. [PMID:10832611]

13. Glavin, G. B. and Hall, A. M. (1994) Clozapine, a dopamine DA4 receptor antagonist, reduces gastric acid secretion and stress-induced gastric mucosal injury. Life Sci, 54: PL261-PL264. [PMID:8152334]

14. Hidaka, K; Matsumoto, M; Tada, S; Tasaki, Y; Yamaguchi, T. (1995) Differential effects of [3H]nemonapride and [3H]spiperone binding on human dopamine D4 receptors. Neurosci. Lett., 186 (2-3): 145-8. [PMID:7777184]

15. Kortagere, S., Gmeiner, P., Weinstein, H. and Schetz, J. A. (2004) Certain 1,4-disubstituted aromatic piperidines and piperazines with extreme selectivity for the dopamine D4 receptor interact with a common receptor microdomain. Mol Pharmacol, 66: 1491-1499. [PMID:15448188]

16. Kulagowski, JJ; Broughton, HB; Curtis, NR; Mawer, IM; Ridgill, MP; Baker, R; Emms, F; Freedman, SB; Marwood, R; Patel, S; et al.. (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]

17. Lahti, R. A., Evans, D. L., Stratman, N. C. and Figur, L. M. (1993) Dopamine D4 versus D2 receptor selectivity of dopamine receptor antagonists: possible therapeutic implications. Eur J Pharmacol, 236: 483-486. [PMID:8102973]

18. Lanau, F., Zenner, M. T., Civelli, O. and Hartman, D. S. (1997) Epinephrine and norepinephrine act as potent agonists at the recombinant human dopamine D4 receptor. J Neurochem, 68: 804-812. [PMID:9003072]

19. Livak, K. J., Rogers, J. and Lichter, J.B. (1995) Variability of dopamine D4 receptor (DRD4) gene sequence within and among nonhuman primate species. Proc. Natl. Acad. Sci. U.S.A., 92: 427-431. [PMID:7831304]

20. McAllister, G., Knowles, M. R., Ward-Booth, S. M., Sinclair, H. A., Patel, S., Marwood, R., Emms, F., Patel, S., Smith, A. and Seabrook, G. R. (1995) Functional coupling of human D2, D3, and D4 dopamine receptors in HEK293 cells. J Recept Signal Transduct Res, 15: 267-281. [PMID:8903944]

21. Meador-Woodruff, J. H., Damask, S. P., Wang, J., Haroutunian, V., Davis, K. L. and Watson, S. J. (1996) Dopamine receptor mRNA expression in human striatum and neocortex. Neuropsychopharmacology, 15: 17-29. [PMID:8797188]

22. Mei, Y. A., Griffon, N., Buquet, C., Martres, M. P., Vaudry, H., Schwartz, J. C., Sokoloff, P. and Cazin, L. (1995) Activation of dopamine D4 receptor inhibits an L-type calcium current in cerebellar granule cells. Neuroscience, 68: 107-116. [PMID:7477916]

23. Millan, M. J., Maiofiss, L., Cussac, D., Audinot, V., Boutin, J. A. and Newman-Tancredi, A. (2002) Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor. I. A multivariate analysis of the binding profiles of 14 drugs at 21 native and cloned human receptor subtypes. J Pharmacol Exp Ther, 303: 791-804. [PMID:12388666]

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26. Nir, I., Harrison, J. M., Haque, R., Low, M. J., Grandy, D. K., Rubinstein, M. and Iuvone, P. M. (2002) Dysfunctional light-evoked regulation of cAMP in photoreceptors and abnormal retinal adaptation in mice lacking dopamine D4 receptors. J Neurosci, 22: 2063-2073. [PMID:11896146]

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33. Ricci, A., Mignini, F., Tomassoni, D. and Amenta, F. (2006) Dopamine receptor subtypes in the human pulmonary arterial tree. Auton Autacoid Pharmacol, 26: 361-369. [PMID:16968475]

34. Rivera, A., Trías, S., Penafiel, A., Angel Narváez, J., Díaz-Cabiale, Z., Moratalla, R. and de la Calle, A. (2003) Expression of D4 dopamine receptors in striatonigral and striatopallidal neurons in the rat striatum. Brain Res, 989: 35-41. [PMID:14519509]

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36. Rubinstein, M., Phillips, T. J., Bunzow, J. R., Falzone, T. L., Dziewczapolski, G., Zhang, G., Fang, Y., Larson, J. L., McDougall, J. A., Chester, J. A., Saez, C., Pugsley, T. A., Gershanik, O., Low, M. J. and Grandy, D. K. (1997) Mice lacking dopamine D4 receptors are supersensitive to ethanol, cocaine, and methamphetamine. Cell, 90: 991-1001. [PMID:9323127]

37. Schetz, J. A., Benjamin, P. S. and Sibley, D. R. (2000) Nonconserved residues in the second transmembrane-spanning domain of the D(4) dopamine receptor are molecular determinants of D(4)-selective pharmacology. Mol Pharmacol, 57: 144-152. [PMID:10617689]

38. Schlachter, S. K., Poel, T. J., Lawson, C. F., Dinh, D. M., Lajiness, M. E., Romero, A. G., Rees, S. A., Duncan, J. N. and Smith, M. W. (1997) Substituted 4-aminopiperidines having high in vitro affinity and selectivity for the cloned human dopamine D4 receptor. Eur J Pharmacol, 322: 283-286. [PMID:9098699]

39. Seeman, P., Guan, H. C., Van Tol, H. H. and Niznik, H. B. (1993) Low density of dopamine D4 receptors in Parkinson's, schizophrenia, and control brain striata. Synapse, 14: 247-253. [PMID:8248849]

40. Shih, Y. H., Chung, F. Z. and Pugsley, T. A. (1997) Cloning, expression and characterization of a human dopamine D4.2 receptor (CHO K1 cells) and various D4.2/D2L chimeras (COS-7 cells). Prog Neuropsychopharmacol Biol Psychiatry, 21: 153-167. [PMID:9075264]

41. Shin, Y., Kumar, U., Patel, Y., Patel, S. C. and Sidhu, A. (2003) Differential expression of D2-like dopamine receptors in the kidney of the spontaneously hypertensive rat. J Hypertens, 21: 199-207. [PMID:12544452]

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To cite this database page, please use the following:

Arvid Carlsson, Marc Caron, Olivier Civelli, John W. Kebabian, Saloman Z. Langer, Bernard Scatton, Jean-Charles Schwartz, Goran Sedvall, Philip Seeman, Pierre Sokoloff, Pierre F. Spano, Hubert H. M. Van Tol.
Dopamine receptors: D4 receptor. Last modified on 31/01/2013. Accessed on 23/05/2013. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=217.


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