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Aliases | DRD1, dopamine receptor D1, DADR, DRD1A | ||||||||||||||||||||||||||||||||||||||||||||||||||
External IDs | OMIM: 126449; MGI: 99578; HomoloGene: 30992; GeneCards: DRD1; OMA:DRD1 - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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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.[5][6][7][8]
Tissue distribution
[edit]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).[9]
Lower levels occur in the basolateral amygdala, cerebral cortex, septum, thalamus, and hypothalamus.[9]
Function
[edit]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.[10][8]
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
[edit]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
[edit]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).[11] D1 receptor has a high degree of structural homology to another dopamine receptor, D5, and they both bind similar drugs.[12] 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.[11] 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.[13]
Agonists
[edit]![](https://upload.wikimedia.org/wikipedia/commons/thumb/d/df/D1_agonists.png/320px-D1_agonists.png)
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.[16] 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.[16][17][18] In 2017, Pfizer made public information about pharmaceutically-acceptable non-catechol selective D1 agonists that are in clinical development.
List of D1 receptor agonists
[edit]- Dihydrexidine derivatives
- A-86929 – full agonist with 14-fold selectivity for D1-like receptors over D2[11][15][19]
- 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.[20][21] It also showed profound antiparkinson effects in MPTP-treated primates,[22] but caused profound hypotension in one early clinical trial in Parkinson's disease.[11] Although dihydrexidine has significant D2 properties, it is highly biased at D1 receptors and was used for the first demonstration of functional selectivity[23] with dopamine receptors.[24][25]
- Dinapsoline – full agonist with 5-fold selectivity for D1-like receptors over D2[11]
- Dinoxyline – full agonist with approximately equal affinity for D1-like and D2 receptors[11]
- Doxanthrine – full agonist with 168-fold selectivity for D1-like receptors over D2[11]
- Benzazepine derivatives
- SKF-81297 – 200-fold selectivity for D1 over any other receptor[11]
- SKF-82958 – 57-fold selectivity for D1 over D2[11]
- SKF-38393 – very high selectivity for D1 with negligible affinity for any other receptor[11]
- Clozapine – partial agonist at D1-like receptors[26]
- Fenoldopam – highly selective peripheral D1 receptor partial agonist used clinically as an antihypertensive[11]
- 6-Br-APB – 90-fold selectivity for D1 over D2[11]
- 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[27]
- 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[28]) has been described that allows reversible control of dopaminergic transmission in wildtype animals.
Antagonists
[edit]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
[edit]- Benzazepine derivatives
- SCH-23,390 – 100-fold selectivity for D1 over D5[11]
- Ecopipam (SCH-39,166) – a selective D1/D5 antagonist that was being developed as an anti-obesity medication but was discontinued[11] However, it has showed promise in reducing stuttering and is currently in Phase 2 Trials for this purpose[29][30]
Modulators
[edit]- DETQ – PAM[31][32][33]
- LY-3154207 – potent and subtype selective PAM, in phase 2 studies for Lewy body dementia.[34]
Protein–protein interactions
[edit]Dopamine receptor D1 has been shown to interact with:
Receptor oligomers
[edit]The D1 receptor forms heteromers with the following receptors: dopamine D2 receptor,[37] dopamine D3 receptor,[37][38] histamine H3 receptor,[39] μ opioid receptor,[40] NMDA receptor,[37] and adenosine A1 receptor.[37]
- D1–D2 receptor complex[37]
- D1−H3−NMDAR receptor complex – a target to prevent neurodegeneration[41]
- D1–D3 receptor complex[37]
- D1–NMDAR receptor complex[37]
- D1–A1 receptor complex[37]
Structure
[edit]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.[42]
![](https://upload.wikimedia.org/wikipedia/commons/thumb/c/c6/Dopamine_d1_receptor_in_complex_with_agonist_dopamine.png/400px-Dopamine_d1_receptor_in_complex_with_agonist_dopamine.png)
See also
[edit]References
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- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000021478 – Ensembl, May 2017
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Dopamine D1 receptor hetero-oligomers - ^ 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 (September 2008). "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. doi:10.1074/jbc.M710349200. PMC 2533781. PMID 18644790.
- ^ Ferrada C, Moreno E, Casadó V, Bongers G, Cortés A, Mallol J, Canela EI, Leurs R, Ferré S, Lluís C, Franco R (May 2009). "Marked changes in signal transduction upon heteromerization of dopamine D1 and histamine H3 receptors". British Journal of Pharmacology. 157 (1): 64–75. doi:10.1111/j.1476-5381.2009.00152.x. PMC 2697789. PMID 19413572.
- ^ Juhasz JR, Hasbi A, Rashid AJ, So CH, George SR, O'Dowd BF (March 2008). "Mu-opioid receptor heterooligomer formation with the dopamine D1 receptor as directly visualized in living cells". European Journal of Pharmacology. 581 (3): 235–243. doi:10.1016/j.ejphar.2007.11.060. PMID 18237729.
- ^ Rodríguez-Ruiz M, Moreno E, Moreno-Delgado D, Navarro G, Mallol J, Cortés A, Lluís C, Canela EI, Casadó V, McCormick PJ, Franco R (August 2017). "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" (PDF). Molecular Neurobiology. 54 (6): 4537–4550. doi:10.1007/s12035-016-9995-y. PMID 27370794. S2CID 11203108.
- ^ Sibley DR, Luderman KD, Free RB, Shi L (May 2021). "Novel Cryo-EM structures of the D1 dopamine receptor unlock its therapeutic potential". Signal Transduction and Targeted Therapy. 6 (1): 205. doi:10.1038/s41392-021-00630-3. PMC 8141052. PMID 34023856.
- ^ Zhuang Y, Krumm B, Zhang H, Zhou XE, Wang Y, Huang XP, Liu Y, Cheng X, Jiang Y, Jiang H, Zhang C, Yi W, Roth BL, Zhang Y, Xu HE (May 2021). "Mechanism of dopamine binding and allosteric modulation of the human D1 dopamine receptor". Cell Research. 31 (5): 593–596. doi:10.1038/s41422-021-00482-0. PMC 8089099. PMID 33750903.
External links
[edit]- "Dopamine Receptors: D1". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Archived from the original on 2015-01-02. Retrieved 2008-12-04.
- Receptors,+Dopamine+D1 at the U.S. 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.