Biology:Dopamine receptor D1

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Short description: Protein-coding gene in humans


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Dopamine receptor D1, also known as DRD1. It is one of the two types of D1-like receptor family — receptors D1 and D5. It is a protein that in humans is encoded by the DRD1 gene.[1][2][3][4]

Tissue distribution

D1 receptors are the most abundant kind of dopamine receptor in the central nervous system.

Northern blot and in situ hybridization show that the mRNA expression of DRD1 is highest in the dorsal striatum (caudate and putamen) and ventral striatum (nucleus accumbens and olfactory tubercle).[5]

Lower levels occur in the basolateral amygdala, cerebral cortex, septum, thalamus, and hypothalamus.[5]

Function

D1 receptors regulate the memory, learning, and the growth of neurons, also is used in the reward system and locomotor activity, mediating some behaviors and modulating dopamine receptor D2-mediated events.[6][4]

They play a role in addiction by facilitating the gene expression changes that occur in the nucleus accumbens during addiction.

They are Gs/a coupled and can stimulate neurons by indirectly activating cyclic AMP-dependent protein kinase.

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).[7] D1 receptor has a high degree of structural homology to another dopamine receptor, D5, and they both bind similar drugs.[8] As a result, none of the known orthosteric 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.[7] Some of the benzazepines have high intrinsic activity whereas others do not. In 2015 the first positive allosteric modulator for the human D1 receptor was discovered by high-throughput screening.[9]

Agonists

Chemical structures of selective D1 receptor agonists[10][11]

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.[12] The selective D1 agonists give profound antiparkinson effects in humans and primate models of PD, and yield cognitive enhancement in many preclinical models and a few clinical trials. The most dose-limiting feature is profound hypotension, but the clinical development was impeded largely by lack of oral bioavailability and short duration of action.[12][13][14] In 2017, Pfizer made public information about pharmaceutically-acceptable non-catechol selective D1 agonists that are in clinical development.

List of D1 receptor agonists

  • Dihydrexidine derivatives
    • A-86929 – full agonist with 14-fold selectivity for D1-like receptors over D2[7][11][15]
    • 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.[16][17] It also showed profound antiparkinson effects in MPTP-treated primates,[18] but caused profound hypotension in one early clinical trial in Parkinson's disease.[7] Although dihydrexidine has significant D2 properties, it is highly biased at D2 receptors and was used for the first demonstration of functional selectivity[19] with dopamine receptors.[20][21]
    • Dinapsoline – full agonist with 5-fold selectivity for D1-like receptors over D2[7]
    • Dinoxyline – full agonist with approximately equal affinity for D1-like and D2 receptors[7]
    • Doxanthrine – full agonist with 168-fold selectivity for D1-like receptors over D2[7]
  • Benzazepine derivatives
    • SKF-81297 – 200-fold selectivity for D1 over any other receptor[7]
    • SKF-82958 – 57-fold selectivity for D1 over D2[7]
    • SKF-38393 – very high selectivity for D1 with negligible affinity for any other receptor[7]
    • Clozapine – partial agonist at D1-like receptors[22]
    • Fenoldopam – highly selective peripheral D1 receptor partial agonist used clinically as an antihypertensive[7]
    • 6-Br-APB – 90-fold selectivity for D1 over D2[7]
  • 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
    • A photoswitchable agonist of D1-like receptors (azodopa[24]) has been described that allows reversible control of dopaminergic transmission in wildtype animals.

Antagonists

Many typical and atypical antipsychotics are D1 receptor antagonists in addition to D2 receptor antagonists. But asenapine has shown stronger D1 receptor affinity compared to other antipsychotics. 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[7]
    • Ecopipam (SCH-39,166) – a selective D1/D5 antagonist that was being developed as an anti-obesity medication but was discontinued[7] However, it has showed promise in reducing stuttering and is currently in Phase 2 Trials for this purpose[25][26]

Modulators

  • DETQ – PAM[27][28][29]
  • LY-3154207 – potent and subtype selective PAM, in phase 2 studies for Lewy body dementia.[30]

Protein–protein interactions

Dopamine receptor D1 has been shown to interact with:

Receptor oligomers

The D1 receptor forms heteromers with the following receptors: dopamine D2 receptor,[33] dopamine D3 receptor,[33][34] histamine H3 receptor,[35] μ opioid receptor,[36] NMDA receptor,[33] and adenosine A1 receptor.[33]

  • D1–D2 receptor complex[33]
  • D1−H3−NMDAR receptor complex – a target to prevent neurodegeneration[37]
  • D1–D3 receptor complex[33]
  • D1–NMDAR receptor complex[33]
  • D1–A1 receptor complex[33]

Structure

Several CryoEM structures of agonists bound to the dopamine D1 receptor complexed with the stimulatory heterotrimeric Gs protein have been determined. Agonist interact with extracellular loop 2 and extracellular regions of trans-membrane helices 2, 3, 6, and 7. Interactions between catechol-based agonists and three trans-membrane serine residues including S1985.42, S1995.43, and S2025.46 function as microswitches that are essential for receptor activation.[38]

Dopamine D1 CryoEM structure in complex with dopamine (PDB code: 7LJD), Dopamine D1 receptor in orange, dopamine in cyan, interactions are in green.[39]

See also

References

  1. ↑ "Molecular cloning and expression of the gene for a human D1 dopamine receptor". Nature 347 (6288): 72–76. September 1990. doi:10.1038/347072a0. PMID 2144334. Bibcode: 1990Natur.347...72D. 
  2. ↑ "Cloning and expression of human and rat D1 dopamine receptors". Nature 347 (6288): 76–80. September 1990. doi:10.1038/347076a0. PMID 2168520. Bibcode: 1990Natur.347...76Z. 
  3. ↑ "Human dopamine D1 receptor encoded by an intronless gene on chromosome 5". Nature 347 (6288): 80–83. September 1990. doi:10.1038/347080a0. PMID 1975640. Bibcode: 1990Natur.347...80S. 
  4. ↑ 4.0 4.1 "Physiological and Functional Basis of Dopamine Receptors and Their Role in Neurogenesis: Possible Implication for Parkinson's disease". Journal of Experimental Neuroscience 12: 1179069518779829. 2018-05-31. doi:10.1177/1179069518779829. PMID 29899667. 
  5. ↑ 5.0 5.1 "Chapter 7: Dopaminergic Neurotransmission". Handbook of Contemporary Neuropharmacology. Hoboken, NJ: Wiley-Interscience. 2007. p. 226. ISBN 9780471660538. "Localization of the D1 receptor messenger ribonucleic acid (mRNA) expression has been mapped using Northern analysis and in situ hybridization (for a review, see [54]). Expression of D1 receptor mRNA is highest in the caudate putamen, nucleus accumbens, and olfactory tubercle. Lower levels of expression are found in the basolateral amygdala, cerebral cortex, septum pellucidum, thalamus, and hypothalamus." 
  6. ↑ "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. October 1992. doi:10.1523/JNEUROSCI.12-10-03729.1992. PMID 1357113. 
  7. ↑ 7.00 7.01 7.02 7.03 7.04 7.05 7.06 7.07 7.08 7.09 7.10 7.11 7.12 7.13 "Dopamine D1 receptor ligands: where are we now and where are we going". Medicinal Research Reviews 29 (2): 272–294. March 2009. doi:10.1002/med.20130. PMID 18642350. 
  8. ↑ "Cloning of the gene for a human dopamine D5 receptor with higher affinity for dopamine than D1". Nature 350 (6319): 614–619. April 1991. doi:10.1038/350614a0. PMID 1826762. Bibcode: 1991Natur.350..614S. 
  9. ↑ "Discovery of D1 Dopamine Receptor Positive Allosteric Modulators: Characterization of Pharmacology and Identification of Residues that Regulate Species Selectivity". The Journal of Pharmacology and Experimental Therapeutics 354 (3): 340–349. September 2015. doi:10.1124/jpet.115.224071. PMID 26109678. 
  10. ↑ "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". Journal of Medicinal Chemistry 49 (23): 6848–6857. November 2006. doi:10.1021/jm0604979. PMID 17154515. 
  11. ↑ 11.0 11.1 "(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 D1 agonist that maintains behavioral efficacy following repeated administration and characterization of its diacetyl prodrug (ABT-431)". Journal of Medicinal Chemistry 38 (18): 3445–3447. September 1995. doi:10.1021/jm00018a002. PMID 7658429. 
  12. ↑ 12.0 12.1 "Effects of the D1 dopamine receptor agonist dihydrexidine (DAR-0100A) on working memory in schizotypal personality disorder". Neuropsychopharmacology 40 (2): 446–453. January 2015. doi:10.1038/npp.2014.192. PMID 25074637. 
  13. ↑ "Effects of the full dopamine D1 receptor agonist dihydrexidine in Parkinson's disease". Clinical Neuropharmacology 21 (6): 339–343. 1998. PMID 9844789. 
  14. ↑ "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. 2006. doi:10.1111/j.1527-3458.2001.tb00201.x. PMID 11607045. 
  15. ↑ "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". Journal of the American Chemical Society 126 (7): 1954–1955. February 2004. doi:10.1021/ja031760n. PMID 14971926. 
  16. ↑ "A single 20 mg dose of the full D1 dopamine agonist dihydrexidine (DAR-0100) increases prefrontal perfusion in schizophrenia". Schizophrenia Research 94 (1–3): 332–341. August 2007. doi:10.1016/j.schres.2007.03.033. PMID 17596915. 
  17. ↑ "A single 20 mg dose of dihydrexidine (DAR-0100), a full dopamine D1 agonist, is safe and tolerated in patients with schizophrenia". Schizophrenia Research 93 (1–3): 42–50. July 2007. doi:10.1016/j.schres.2007.03.011. PMID 17467956. 
  18. ↑ "Dihydrexidine, a full dopamine D1 agonist, reduces MPTP-induced parkinsonism in monkeys". European Journal of Pharmacology 199 (3): 389–391. July 1991. doi:10.1016/0014-2999(91)90508-N. PMID 1680717. 
  19. ↑ "Functional selectivity and classical concepts of quantitative pharmacology". The Journal of Pharmacology and Experimental Therapeutics 320 (1): 1–13. January 2007. doi:10.1124/jpet.106.104463. PMID 16803859. https://cdr.lib.unc.edu/downloads/j9602272s. 
  20. ↑ "Functional selectivity of dopamine receptor agonists. I. Selective activation of postsynaptic dopamine D2 receptors linked to adenylate cyclase". The Journal of Pharmacology and Experimental Therapeutics 301 (3): 1166–1178. June 2002. doi:10.1124/jpet.301.3.1166. PMID 12023552. 
  21. ↑ "Functional selectivity of dopamine receptor agonists. II. Actions of dihydrexidine in D2L receptor-transfected MN9D cells and pituitary lactotrophs". The Journal of Pharmacology and Experimental Therapeutics 301 (3): 1179–1189. June 2002. doi:10.1124/jpet.301.3.1179. PMID 12023553. 
  22. ↑ "Clozapine: dopamine D1 receptor agonism in the prefrontal cortex as the code to decipher a Rosetta stone of antipsychotic drugs". Pharmacology & Toxicology 84 (5): 193–196. May 1999. doi:10.1111/j.1600-0773.1999.tb01482.x. PMID 10361974. 
  23. ↑ "Facile synthesis of octahydrobenzo[hisoquinolines: novel and highly potent D1 dopamine agonists"]. Bioorganic & Medicinal Chemistry 18 (18): 6763–6770. September 2010. doi:10.1016/j.bmc.2010.07.052. PMID 20709559. 
  24. ↑ "Reversible Photocontrol of Dopaminergic Transmission in Wild-Type Animals" (in en). International Journal of Molecular Sciences 23 (17): 10114. January 2022. doi:10.3390/ijms231710114. ISSN 1422-0067. PMID 36077512. 
  25. ↑ Maguire, G. A.; Lasalle, L.; Hoffmeyer, D.; Nelson, M.; Lochhead, J. D.; Davis, K.; Burris, A.; Yaruss, J. S. (2019). "Ecopipam as a pharmacologic treatment of stuttering". Annals of Clinical Psychiatry 31 (3): 164–168. PMID 31369655. https://pubmed.ncbi.nlm.nih.gov/31369655/. 
  26. ↑ "First Patient Dosed in Emalex Biosciences Phase 2 Clinical Trial for Stuttering - Emalex Biosciences". 15 December 2020. https://emalexbiosciences.com/news/first-patient-dosed-in-emalex-biosciences-phase-2-clinical-trial-for-stuttering/. 
  27. ↑ "An Allosteric Potentiator of the Dopamine D1 Receptor Increases Locomotor Activity in Human D1 Knock-In Mice without Causing Stereotypy or Tachyphylaxis". The Journal of Pharmacology and Experimental Therapeutics 360 (1): 117–128. January 2017. doi:10.1124/jpet.116.236372. PMID 27811173. 
  28. ↑ "Preclinical profile of a dopamine D1 potentiator suggests therapeutic utility in neurological and psychiatric disorders". Neuropharmacology 128: 351–365. January 2018. doi:10.1016/j.neuropharm.2017.10.032. PMID 29102759. 
  29. ↑ "Intracellular Binding Site for a Positive Allosteric Modulator of the Dopamine D1 Receptor". Molecular Pharmacology 94 (4): 1232–1245. October 2018. doi:10.1124/mol.118.112649. PMID 30111649. 
  30. ↑ "Synthesis and Pharmacological Characterization of 2-(2,6-Dichlorophenyl)-1-((1S,3R)-5-(3-hydroxy-3-methylbutyl)-3-(hydroxymethyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one (LY3154207), a Potent, Subtype Selective, and Orally Available Positive Allosteric Modulator of the Human Dopamine D1 Receptor". Journal of Medicinal Chemistry 62 (19): 8711–8732. October 2019. doi:10.1021/acs.jmedchem.9b01234. PMID 31532644. 
  31. ↑ 31.0 31.1 "Interaction of gamma-COP with a transport motif in the D1 receptor C-terminus". European Journal of Cell Biology 81 (2): 77–85. February 2002. doi:10.1078/0171-9335-00222. PMID 11893085. 
  32. ↑ "Regulation of transport of the dopamine D1 receptor by a new membrane-associated ER protein". Nature Cell Biology 3 (5): 492–498. May 2001. doi:10.1038/35074561. PMID 11331877. 
  33. ↑ 33.0 33.1 33.2 33.3 33.4 33.5 33.6 33.7 "Mechanisms for the modulation of dopamine d(1) receptor signaling in striatal neurons". Frontiers in Neuroanatomy 5: 43. July 2011. doi:10.3389/fnana.2011.00043. PMID 21811441. 
    Dopamine D1 receptor hetero-oligomers
  34. ↑ "Identification of dopamine D1-D3 receptor heteromers. Indications for a role of synergistic D1-D3 receptor interactions in the striatum". The Journal of Biological Chemistry 283 (38): 26016–26025. September 2008. doi:10.1074/jbc.M710349200. PMID 18644790. 
  35. ↑ "Marked changes in signal transduction upon heteromerization of dopamine D1 and histamine H3 receptors". British Journal of Pharmacology 157 (1): 64–75. May 2009. doi:10.1111/j.1476-5381.2009.00152.x. PMID 19413572. 
  36. ↑ "Mu-opioid receptor heterooligomer formation with the dopamine D1 receptor as directly visualized in living cells". European Journal of Pharmacology 581 (3): 235–243. March 2008. doi:10.1016/j.ejphar.2007.11.060. PMID 18237729. 
  37. ↑ "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". Molecular Neurobiology 54 (6): 4537–4550. August 2017. doi:10.1007/s12035-016-9995-y. PMID 27370794. https://ueaeprints.uea.ac.uk/id/eprint/59599/1/Rodriguez_et_ale.Proofing.pdf. 
  38. ↑ "Novel Cryo-EM structures of the D1 dopamine receptor unlock its therapeutic potential". Signal Transduction and Targeted Therapy 6 (1): 205. May 2021. doi:10.1038/s41392-021-00630-3. PMID 34023856. 
  39. ↑ "Mechanism of dopamine binding and allosteric modulation of the human D1 dopamine receptor". Cell Research 31 (5): 593–596. May 2021. doi:10.1038/s41422-021-00482-0. PMID 33750903. 

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