# Dopamine receptor D1

Dopamine receptor D$_1$, also known as DRD1. It is one of the two types of D$_1$-like receptor family — receptors D$_1$ and D$_5$. It is a protein that in humans is encoded by the DRD1 gene.

## Tissue distribution

D$_1$ 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).
Lower levels occur in the basolateral amygdala, cerebral cortex, septum, thalamus, and hypothalamus.

## Function

D$_1$ 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 D$_2$-mediated events.
They play a role in addiction by facilitating the gene expression changes that occur in the nucleus accumbens during addiction.
They are Gs coupled and can stimulate neurons by activation of 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 D$_1$ 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). D$_1$ receptor has a high degree of structural homology to another dopamine receptor, D$_5$, and they both bind similar drugs. As a result, none of the known orthosteric ligands is selective for the D$_1$ vs. the D$_5$ receptor, but the benzazepines generally are more selective for the D$_1$ and D$_5$ receptors versus the D$_2$-like family. Some of the benzazepines have high intrinsic activity whereas others do not. In 2015 the first positive allosteric modulator for the human D$_1$ receptor was discovered by high-throughput screening.

### Agonists

Several D$_1$ receptor agonists are used clinically. These include apomorphine, pergolide, rotigotine, and terguride. All of these drugs are preferentially D$_2$-like receptor agonists. Fenoldopam is a selective D$_1$ 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 D$_1$-like receptor agonists that have been studied clinically in humans. The selective D$_1$ 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. In 2017, Pfizer made public information about pharmaceutically-acceptable non-catechol selective D$_1$ agonists that are in clinical development.

#### List of D$_1$ receptor agonists

* Dihydrexidine derivatives
** A-86929 – full agonist with 14-fold selectivity for D$_1$-like receptors over D$_2$
** Dihydrexidine – full agonist with 10-fold selectivity for D$_1$-like receptors over D$_2$ that has been in Phase IIa clinical trials as a cognitive enhancer. It also showed profound antiparkinson effects in MPTP-treated primates, but caused profound hypotension in one early clinical trial in Parkinson's disease. Although dihydrexidine has significant D$_2$ properties, it is highly biased at D$_1$ receptors and was used for the first demonstration of functional selectivity with dopamine receptors.
** Dinapsoline – full agonist with 5-fold selectivity for D$_1$-like receptors over D$_2$
** Dinoxyline – full agonist with approximately equal affinity for D$_1$-like and D$_2$ receptors
** Doxanthrine – full agonist with 168-fold selectivity for D$_1$-like receptors over D$_2$
* Benzazepine derivatives
** SKF-81297 – 200-fold selectivity for D$_1$ over any other receptor
** SKF-82958 – 57-fold selectivity for D$_1$ over D$_2$
** SKF-38393 – very high selectivity for D$_1$ with negligible affinity for any other receptor
** Clozapine – partial agonist at D$_1$-like receptors
** Fenoldopam – highly selective peripheral D$_1$ receptor partial agonist used clinically as an antihypertensive
** 6-Br-APB – 90-fold selectivity for D$_1$ over D$_2$
** Trepipam (SCH-12679)
* Others
** Stepholidine – alkaloid with D$_1$ agonist and D$_2$ antagonist properties, showing antipsychotic effects
** A-68930
** A-77636
** CY-208,243 – high intrinsic activity partial agonist with moderate selectivity for D$_1$-like over D$_2$-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
** Cabergoline – weak D$_1$ agonism, highly selective for D$_2$, and various serotonin receptors
** Pergolide – (similar to cabergoline) weak D$_1$ agonism, highly selective for D$_2$, and various serotonin receptors
** A photoswitchable agonist of D$_1$-like receptors (azodopa) has been described that allows reversible control of dopaminergic transmission in wildtype animals.

### Positive allosteric modulators

* DETQ – PAM
* Glovadalen (UCB-0022) – selective PAM, in phase 2 studies for Parkinson's disease
* Mevidalen (LY-3154207) – potent and subtype selective PAM, in phase 2 studies for Lewy body dementia.

### Antagonists

Many typical and atypical antipsychotics are D$_1$ receptor antagonists in addition to D$_2$ receptor antagonists. But asenapine has shown stronger D$_1$ receptor affinity compared to other antipsychotics. No other D$_1$ receptor antagonists have been approved for clinical use. Ecopipam is a selective D$_1$-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 D$_1$ receptor antagonists

* Berupipam (NNC 22-0010)
* Ecopipam (SCH-39,166) – a selective D$_1$/D$_5$ antagonist that was being developed as an anti-obesity medication but was discontinued However, it has showed promise in reducing stuttering and is currently in Phase 2 Trials for this purpose
* NNC 01-0687 (ADX-10061)
* Odapipam (NNC 01-0756)
* SCH-23,390 – 100-fold selectivity for D$_1$ over D$_5$

## Protein–protein interactions

Dopamine receptor D$_1$ has been shown to interact with:
* COPG2
* COPG
* DNAJC14

### Receptor oligomers

The D$_1$ receptor forms heteromers with the following receptors: dopamine D$_2$ receptor, dopamine D$_3$ receptor, histamine H$_3$ receptor, μ opioid receptor, NMDA receptor, and adenosine A$_1$ receptor.
* D$_1$–D$_2$ receptor complex
* D$_1$−H$_3$−NMDAR receptor complex – a target to prevent neurodegeneration
* D$_1$–D3 receptor complex
* D$_1$–NMDAR receptor complex
* D$_1$–A$_1$ receptor complex

## 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.