Dopamine receptor D1

DRD1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1OZ5
Identifiers
Aliases	DRD1, dopamine receptor D1, DADR, DRD1A
External IDs	MGI: 99578 HomoloGene: 30992 GeneCards: DRD1
Targeted by Drug
a-68930, apomorphine, cabergoline, dopamine, fenoldopam, pergolide, rotigotine, serotonin, bromocriptine, lisuride, SKF-38393, (+)-butaclamol, chlorpromazine, clozapine, ecopipam, (Z)-flupentixol, fluphenazine, haloperidol, ketanserin, mesoridazine, prochlorperazine, SCH-23390, spiperone, thioridazine[1]
Gene ontology Molecular function • dopamine neurotransmitter receptor activity • dopamine binding • protein binding • dopamine neurotransmitter receptor activity, coupled via Gs • G-protein coupled receptor activity • signal transducer activity Cellular component • membrane • nucleus • endoplasmic reticulum • integral component of membrane • nonmotile primary cilium • plasma membrane • endoplasmic reticulum membrane • integral component of plasma membrane • ciliary membrane • endomembrane system Biological process • positive regulation of cytosolic calcium ion concentration involved in phospholipase C-activating G-protein coupled signaling pathway • muscle contraction • adenylate cyclase-activating G-protein coupled receptor signaling pathway • protein import into nucleus • positive regulation of potassium ion transport • response to amphetamine • learning • synaptic transmission, dopaminergic • feeding behavior • long term synaptic depression • temperature homeostasis • striatum development • prepulse inhibition • response to cocaine • grooming behavior • behavioral response to cocaine • locomotory behavior • dentate gyrus development • transmission of nerve impulse • memory • positive regulation of synaptic transmission, glutamatergic • synapse assembly • habituation • adult walking behavior • peristalsis • cellular response to catecholamine stimulus • G-protein coupled receptor signaling pathway • adenylate cyclase-activating dopamine receptor signaling pathway • regulation of dopamine uptake involved in synaptic transmission • associative learning • astrocyte development • G-protein coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger • positive regulation of release of sequestered calcium ion into cytosol • mating behavior • behavioral fear response • activation of adenylate cyclase activity • dopamine receptor signaling pathway • conditioned taste aversion • cerebral cortex GABAergic interneuron migration • glucose import • visual learning • sensitization • positive regulation of cell migration • operant conditioning • vasodilation • regulation of dopamine metabolic process • dopamine metabolic process • phospholipase C-activating dopamine receptor signaling pathway • maternal behavior • dopamine transport • hippocampus development • response to drug • positive regulation of adenylate cyclase activity involved in G-protein coupled receptor signaling pathway • neuronal action potential • long-term synaptic potentiation • signal transduction • positive regulation of cAMP biosynthetic process Sources:Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	1812	13488
Ensembl	ENSG00000184845	ENSMUSG00000021478
UniProt	P21728	Q61616
RefSeq (mRNA)	NM_000794	NM_001291801 NM_010076
RefSeq (protein)	NP_000785.1	NP_001278730.1 NP_034206.1
Location (UCSC)	Chr 5: 175.44 – 175.44 Mb	Chr 13: 54.05 – 54.06 Mb
PubMed search	[2]	[3]
Wikidata

View/Edit Human

View/Edit Mouse

Dopamine receptor D₁, also known as DRD1, is a protein that in humans is encoded by the DRD1 gene.^[4][5][6]

Function

This gene encodes the D₁ subtype of the dopamine receptor. The D₁ subtype is the most abundant dopamine receptor in the central nervous system. This G protein-coupled receptor stimulates adenylate cyclase and indirectly activates cyclic AMP-dependent protein kinases. D₁ receptors regulate neuronal growth and development, mediate some behavioral responses, and modulate dopamine receptor D₂-mediated events.^[7] Alternative transcription initiation sites result in two transcript variants of this gene.^[8]

Production

The DRD1 gene expresses primarily in the caudate putamen in humans, and in the caudate putamen, the nucleus accumbens and the olfactory tubercle in mouse. Gene expression patterns from the Allen Brain Atlases in mouse and human can be found here.

Ligands

There are a number of ligands selective for the D₁ receptors. To date, most of the known ligands are based on dihydrexidine or the prototypical benzazepine partial agonist SKF-38393 (one derivative being the prototypical antagonist SCH-23390).^[9] D₁ receptor has a high degree of structural homologine to another dopamine receptor, D₅, and they both bind similar drugs.^[10] As a result, none of the known ligands is selective for the D₁ vs. the D₅ receptor, but the benzazepines generally are more selective for the D₁ and D₅ receptors versus the D₂-like family.^[9] Some of the benzazepines have high intrinsic activity whereas others do not.

Agonists

Chemical structures of selective D₁ receptor agonists.^[11][12]

Several D₁ receptor agonists are used clinically. These include apomorphine, pergolide, rotigotine, and terguride. All of these drugs are preferentially D₂-like receptor agonists. Fenoldopam is a selective D₁ receptor partial agonist that does not cross the blood-brain-barrier and is used intravenously in the treatment of hypertension. Dihydrexidine and adrogolide (ABT-431) (a prodrug of A-86929 with improved bioavailability) are the only selective, centrally active D₁-like receptor agonists that have been studied clinically in humans.^[13] They produced dose-limiting profound hypotension and dyskinesias, respectively, and were not further developed for clinical use.^[13][14][15]

List of D₁ receptor agonists

• Dihydrexidine derivatives
  • A-86929 - full agonist with 14-fold selectivity for D₁-like receptors over D₂^[9][12][16]
  • Dihydrexidine - full agonist with 10-fold selectivity for D₁-like receptors over D₂ that has been in Phase IIa clinical trials as a cognitive enhancer.^[17][18] It also showed profound antiparkinson effects in MPTP-treated primates,^[19] but caused profound hypotension in one early clinical trial in Parkinson's disease.^[9] Although dihydrexidine has significant D₂ properties, it is highly biased at D₂ receptors and was used for the first demonstration of functional selectivity^[20] with dopamine receptors.^[21][22]
  • Dinapsoline - full agonist with 5-fold selectivity for D₁-like receptors over D₂^[9]
  • Dinoxyline - full agonist with approximately equal affinity for D₁-like and D₂ receptors^[9]
  • Doxanthrine - full agonist with 168-fold selectivity for D₁-like receptors over D₂^[9]
• Benzazepine derivatives
  • SKF-81297 - 200-fold selectivity for D₁ over any other receptor^[9]
  • SKF-82958 - 57-fold selectivity for D₁ over D₂^[9]
  • SKF-38393 - very high selectivity for D₁ with negligible affinity for any other receptor^[9]
  • Fenoldopam - highly selective peripheral D₁ receptor partial agonist used clinically as an antihypertensive^[9]
  • 6-Br-APB - 90-fold selectivity for D₁ over D₂^[9]
• Others
  • Stepholidine - alkaloid with D1 agonist and D2 antagonist properties, showing antipsychotic effects
  • A-68930
  • A-77636
  • CY-208,243 - high intrinsic activity partial agonist with moderate selectivity for D₁-like over D₂-like receptors, member of ergoline ligand family like pergolide and bromocriptine.
  • SKF-89145
  • SKF-89626
  • 7,8-Dihydroxy-5-phenyl-octahydrobenzo[h]isoquinoline: extremely potent, high-affinity full agonist^[23]
  • Cabergoline - weak D₁ agonism, highly selective for D₂, and various serotonin receptors
  • Pergolide - (similar to cabergoline) weak D₁ agonism, highly selective for D₂, and various serotonin receptors

Antagonists

Many typical and atypical antipsychotics are D₁ receptor antagonists in addition to D₂ receptor antagonists. No other D₁ receptor antagonists have been approved for clinical use. Ecopipam is a selective D₁-like receptor antagonist that has been studied clinically in humans in the treatment of a variety of conditions, including schizophrenia, cocaine abuse, obesity, pathological gambling, and Tourette's syndrome, with efficacy in some of these conditions seen. The drug produced mild-to-moderate, reversible depression and anxiety in clinical studies however and has yet to complete development for any indication.

List of D₁ receptor antagonists

• Benzazepine derivatives
  • SCH-23,390 - 100-fold selectivity for D₁ over D₅^[9]
  • SKF-83,959 - 7-fold selectivity for D₁ over D₅ with negligible affinity for other receptors;^[9] acts as an antagonist at D₁ but as an agonist at D₅
  • Ecopipam (SCH-39,166) - a selective D₁/D₅ antagonist that was being developed as an anti-obesity medication but was discontinued^[9]

Protein–protein interactions

Dopamine receptor D₁ has been shown to interact with:

• COPG2,^[24]
• COPG,^[24] and
• DNAJC14.^[25]

Receptor oligomers

The D₁ receptor forms heteromers with the following receptors: dopamine D₂, D₃,^[26] histamine H₃,^[27] μ opioid.^[28]

• D1–D2
• D1−H3−NMDA receptor complex − a target to prevent neurodegeneration^[29]

See also

• Dopamine receptor

References

1. "Drugs that physically interact with D(1A) dopamine receptor view/edit references on wikidata".
2. "Human PubMed Reference:".
3. "Mouse PubMed Reference:".
4. Dearry A, Gingrich JA, Falardeau P, Fremeau RT, Bates MD, Caron MG (September 1990). "Molecular cloning and expression of the gene for a human D₁ dopamine receptor". Nature. 347 (6288): 72–6. doi:10.1038/347072a0. PMID 2144334.
5. Zhou QY, Grandy DK, Thambi L, Kushner JA, Van Tol HH, Cone R, Pribnow D, Salon J, Bunzow JR, Civelli O (September 1990). "Cloning and expression of human and rat D₁dopamine receptors". Nature. 347 (6288): 76–80. doi:10.1038/347076a0. PMID 2168520.
6. Sunahara RK, Niznik HB, Weiner DM, Stormann TM, Brann MR, Kennedy JL, Gelernter JE, Rozmahel R, Yang YL, Israel Y (September 1990). "Human dopamine D₁ receptor encoded by an intronless gene on chromosome 5". Nature. 347 (6288): 80–3. doi:10.1038/347080a0. PMID 1975640.
7. ML Paul; AM Graybiel; JC David; HA Robertson (1992). "D1-like and D2-like dopamine receptors synergistically activate rotation and c-fos expression in the dopamine-depleted striatum in a rat model of Parkinson's disease". The Journal of Neuroscience. 12 (10): 3729–3742.
8. "Entrez Gene: DRD1 dopamine receptor D₁".
9. Zhang J, Xiong B, Zhen X, Zhang A (2009). "Dopamine D₁ receptor ligands: where are we now and where are we going.". Med Res Rev. 29 (2): 272–294. doi:10.1002/med.20130. PMID 18642350.
10. Sunahara RK, Guan HC, O'Dowd BF, Seeman P, Laurier LG, Ng G, George SR, Torchia J, Van Tol HH, Niznik HB (1991). "Cloning of the gene for a human dopamine D5 receptor with higher affinity for dopamine than D1". Nature. 350 (6319): 614–9. doi:10.1038/350614a0. PMID 1826762.
11. Cueva JP, Giorgioni G, Grubbs RA, Chemel BR, Watts VJ, Nichols DE (November 2006). "trans-2,3-dihydroxy-6a,7,8,12b-tetrahydro-6H-chromeno[3,4-c]isoquinoline: synthesis, resolution, and preliminary pharmacological characterization of a new dopamine D1 receptor full agonist". J. Med. Chem. 49 (23): 6848–57. doi:10.1021/jm0604979. PMID 17154515.
12. Michaelides MR, Hong Y, DiDomenico S, Asin KE, Britton DR, Lin CW, Williams M, Shiosaki K (1995). "(5aR,11bS)-4,5,5a,6,7,11b-hexahydro-2-propyl-3-thia-5-azacyclopent-1- ena[c]-phenanthrene-9,10-diol (A-86929): a potent and selective dopamine D₁agonist that maintains behavioral efficacy following repeated administration and characterization of its diacetyl prodrug (ABT-431)". J. Med. Chem. 38 (18): 3445–7. doi:10.1021/jm00018a002. PMID 7658429.
13. Rosell, Daniel R; Zaluda, Lauren C; McClure, Margaret M; Perez-Rodriguez, M Mercedes; Strike, K Sloan; Barch, Deanna M; Harvey, Philip D; Girgis, Ragy R; Hazlett, Erin A; Mailman, Richard B; Abi-Dargham, Anissa; Lieberman, Jeffrey A; Siever, Larry J (2014). "Effects of the D1 Dopamine Receptor Agonist Dihydrexidine (DAR-0100A) on Working Memory in Schizotypal Personality Disorder". Neuropsychopharmacology. 40 (2): 446–453. doi:10.1038/npp.2014.192. ISSN 0893-133X.
14. Blanchet PJ, Fang J, Gillespie M, Sabounjian L, Locke KW, Gammans R, Mouradian MM, Chase TN (1998). "Effects of the full dopamine D1 receptor agonist dihydrexidine in Parkinson's disease". Clin Neuropharmacol. 21 (6): 339–43. PMID 9844789.
15. Giardina, William J.; Williams, Michael (2006). "Adrogolide HCl (ABT-431; DAS-431), a Prodrug of the Dopamine D1 Receptor Agonist, A-86929: Preclinical Pharmacology and Clinical Data". CNS Drug Reviews. 7 (3): 305–316. doi:10.1111/j.1527-3458.2001.tb00201.x. ISSN 1080-563X.
16. Yamashita M, Yamada K, Tomioka K (2004). "Construction of arene-fused-piperidine motifs by asymmetric addition of 2-trityloxymethylaryllithiums to nitroalkenes: the asymmetric synthesis of a dopamine D₁ full agonist, A-86929". J. Am. Chem. Soc. 126 (7): 1954–5. doi:10.1021/ja031760n. PMID 14971926.
17. Mu Q, Johnson K, Morgan PS, Grenesko EL, Molnar CE, Anderson B, Nahas Z, Kozel FA, Kose S, Knable M, Fernandes P, Nichols DE, Mailman RB, George MS (2007). "A single 20 mg dose of the full D1 dopamine agonist dihydrexidine (DAR-0100) increases prefrontal perfusion in schizophrenia.". Schizophr Res. 94 (1-3): 332–341. doi:10.1016/j.schres.2007.03.033. PMID 17596915.
18. George MS, Molnar CE, Grenesko EL, Anderson B, Mu Q, Johnson K, Nahas Z, Knable M, Fernandes P, Juncos J, Huang X, Nichols DE, Mailman RB (2007). "A single 20 mg dose of dihydrexidine (DAR-0100), a full dopamine D1 agonist, is safe and tolerated in patients with schizophrenia.". Schizophr Res. 93 (1-3): 42–50. doi:10.1016/j.schres.2007.03.011. PMID 17467956.
19. Taylor JR, Lawrence MS, Redmond DE, Elsworth JD, Roth RH, Nichols DE, Mailman RB (1991). "Dihydrexidine, a full dopamine D1 agonist, reduces MPTP-induced parkinsonism in monkeys.". Eur J Pharmacol. 199 (3): 389–391. doi:10.1016/0014-2999(91)90508-N. PMID 1680717.
20. Urban JD, Clarke WP, von Zastrow M, Nichols DE, Kobilka B, Weinstein H, Javitch JA, Roth BL, Christopoulos A, Sexton PM, Miller KJ, Spedding M, Mailman RB (January 2007). "Functional selectivity and classical concepts of quantitative pharmacology". J. Pharmacol. Exp. Ther. 320 (1): 1–13. doi:10.1124/jpet.106.104463. PMID 16803859.
21. Mottola DM, Kilts JD, Lewis MM, Connery HS, Walker QD, Jones SR, Booth RG, Hyslop DK, Piercey M, Wightman RM, Lawler CP, Nichols DE, Mailman RB (June 2002). "Functional selectivity of dopamine receptor agonists. I. Selective activation of postsynaptic dopamine D2 receptors linked to adenylate cyclase". J. Pharmacol. Exp. Ther. 301 (3): 1166–78. doi:10.1124/jpet.301.3.1166. PMID 12023552.
22. Kilts JD, Connery HS, Arrington EG, Lewis MM, Lawler CP, Oxford GS, O'Malley KL, Todd RD, Blake BL, Nichols DE, Mailman RB (June 2002). "Functional selectivity of dopamine receptor agonists. II. Actions of dihydrexidine in D2L receptor-transfected MN9D cells and pituitary lactotrophs". J. Pharmacol. Exp. Ther. 301 (3): 1179–89. doi:10.1124/jpet.301.3.1179. PMID 12023553.
23. Bonner LA, Chemel BR, Watts VJ, Nichols DE (September 2010). "Facile synthesis of octahydrobenzo[h]isoquinolines: novel and highly potent D1 dopamine agonists". Bioorg. Med. Chem. 18 (18): 6763–70. doi:10.1016/j.bmc.2010.07.052. PMC 2941879. PMID 20709559.
24. Bermak JC, Li M, Bullock C, Weingarten P, Zhou QY (Feb 2002). "Interaction of gamma-COP with a transport motif in the D1 receptor C-terminus". Eur. J. Cell Biol. 81 (2): 77–85. doi:10.1078/0171-9335-00222. PMID 11893085.
25. Bermak JC, Li M, Bullock C, Zhou QY (May 2001). "Regulation of transport of the dopamine D1 receptor by a new membrane-associated ER protein". Nat. Cell Biol. 3 (5): 492–8. doi:10.1038/35074561. PMID 11331877.
26. Marcellino D, Ferré S, Casadó V, Cortés A, Le Foll B, Mazzola C, Drago F, Saur O, Stark H, Soriano A, Barnes C, Goldberg SR, Lluis C, Fuxe K, Franco R (2008). "Identification of dopamine D1-D3 receptor heteromers. Indications for a role of synergistic D1-D3 receptor interactions in the striatum". J. Biol. Chem. 283 (38): 26016–25. doi:10.1074/jbc.M710349200. PMC 2533781. PMID 18644790.
27. Ferrada C, Moreno E, Casadó V, Bongers G, Cortés A, Mallol J, Canela EI, Leurs R, Ferré S, Lluís C, Franco R (2009). "Marked changes in signal transduction upon heteromerization of dopamine D1 and histamine H3 receptors". Br. J. Pharmacol. 157 (1): 64–75. doi:10.1111/j.1476-5381.2009.00152.x. PMC 2697789. PMID 19413572.
28. Juhasz JR, Hasbi A, Rashid AJ, So CH, George SR, O'Dowd BF (2008). "Mu-opioid receptor heterooligomer formation with the dopamine D1 receptor as directly visualized in living cells". Eur. J. Pharmacol. 581 (3): 235–43. doi:10.1016/j.ejphar.2007.11.060. PMID 18237729.
29. Rodríguez-Ruiz M, Moreno E, Moreno-Delgado D, Navarro G, Mallol J, Cortés A, Lluís C, Canela EI, Casadó V, McCormick PJ, Franco R (2016). "Heteroreceptor Complexes Formed by Dopamine D1, Histamine H3, and N-Methyl-D-Aspartate Glutamate Receptors as Targets to Prevent Neuronal Death in Alzheimer's Disease". Mol. Neurobiol. doi:10.1007/s12035-016-9995-y. PMID 27370794.

External links

• "Dopamine Receptors: D₁". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.
• Receptors, Dopamine D1 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.