Dopamine receptor D₁

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]

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.

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.

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]

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.

• 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.

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.

• 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]

• DETQ – PAM^[31][32][33]
• LY-3154207 – potent and subtype selective PAM, in phase 2 studies for Lewy body dementia.^[34]

Dopamine receptor D₁ has been shown to interact with:

• COPG2^[35]
• COPG^[35]
• DNAJC14^[36]

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]

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]

• Dopamine receptor

• "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.