Dopamine receptor D<sub>1</sub>, also known as DRD1, is one of the two types of D<sub>1</sub>-like receptor familyreceptors D<sub>1</sub> and D<sub>5</sub>. It is a protein that in humans is encoded by the DRD1 gene.
D<sub>1</sub> 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.
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.
The dopamine receptor D1 (D1R) is a Gs-coupled GPCR characterized by a canonical seven-transmembrane (TM) helical domain, with a ligand-binding pocket located extracellularly and a cytoplasmic G-protein interaction interface. Cryo-EM and X-ray crystallography studies reveal that agonist binding induces conformational changes, including outward movement of TM6 and extension of TM5 by two helical turns, facilitating engagement with the Gñs subunit.
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 S198<sup>5.42</sup>, S199<sup>5.43</sup>, and S202<sup>5.46</sup> function as microswitches that are essential for receptor activation.
The ligand-binding pocket accommodates both catechol (e.g., dopamine, SKF81297) and non-catechol agonists, with selectivity influenced by residues like V317<sup>7.39</sup> and W321<sup>7.43</sup> in TM7, which form hydrophobic interactions rather than the polar contacts seen in ò2-adrenergic receptors. Non-catechol agonists bind in an extended conformation, spanning the orthosteric site to extracellular loop 2 (ECL2), leveraging unique pocket topology for D1R specificity. Structural comparisons with D2R highlight divergent cytoplasmic featuresâÂÂD1R's elongated TM5 and larger Gs interface (~1,520 à<sup>2</sup>) contrast with D2R's Gi-selective coupling, underpinning functional specificity. These insights provide templates for designing selective therapeutics targeting dopaminergic pathways.
D<sub>1</sub> 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<sub>2</sub>-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.
There are a number of ligands selective for the D<sub>1</sub> 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<sub>1</sub> receptor has a high degree of structural homology to another dopamine receptor, D<sub>5</sub>, and they both bind similar drugs. As a result, none of the known orthosteric ligands is selective for the D<sub>1</sub> vs. the D<sub>5</sub> receptor, but the benzazepines generally are more selective for the D<sub>1</sub> and D<sub>5</sub> receptors versus the D<sub>2</sub>-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<sub>1</sub> receptor was discovered by high-throughput screening.
Several D<sub>1</sub> receptor agonists are used clinically. These include apomorphine, pergolide, rotigotine, and terguride. All of these drugs are preferentially D<sub>2</sub>-like receptor agonists. Fenoldopam is a selective D<sub>1</sub> 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<sub>1</sub>-like receptor agonists that have been studied clinically in humans. The selective D<sub>1</sub> 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<sub>1</sub> agonists that are in clinical development.
Many typical and atypical antipsychotics are D<sub>1</sub> receptor antagonists in addition to D<sub>2</sub> receptor antagonists. But asenapine has shown stronger D<sub>1</sub> receptor affinity compared to other antipsychotics. No other D<sub>1</sub> receptor antagonists have been approved for clinical use. Ecopipam is a selective D<sub>1</sub>-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.
Dopamine receptor D<sub>1</sub> has been shown to interact with:
The D<sub>1</sub> receptor forms heteromers with the following receptors: dopamine D<sub>2</sub> receptor, dopamine D<sub>3</sub> receptor, histamine H<sub>3</sub> receptor, ü opioid receptor, NMDA receptor, and adenosine A<sub>1</sub> receptor.