Dopamine receptor D1
Dopamine receptor D, 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. 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). Lower levels occur in the basolateral amygdala, cerebral cortex, septum, thalamus, and hypothalamus. 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. 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 D 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 receptor has a high degree of structural homology to another dopamine receptor, D, and they both bind similar drugs. As a result, none of the known orthosteric ligands is selective for the D vs. the D receptor, but the benzazepines generally are more selective for the D and D receptors versus the  D-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 receptor was discovered by high-throughput screening. Agonists. Several D receptor agonists are used clinically. These include apomorphine, pergolide, rotigotine, and terguride. All of these drugs are preferentially D-like receptor agonists. Fenoldopam is a selective D 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-like receptor agonists that have been studied clinically in humans. The selective D 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 agonists that are in clinical development. Antagonists. Many typical and atypical antipsychotics are D receptor antagonists in addition to D receptor antagonists. No  other D receptor antagonists have been approved for clinical use. Ecopipam is a selective D-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. Protein–protein interactions. Dopamine receptor D has been shown to interact with: Receptor oligomers. The D receptor forms heteromers with the following receptors: dopamine D  receptor, dopamine D receptor, histamine H receptor, μ opioid receptor, NMDA receptor, and adenosine A receptor. 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.