Dopamine receptor D1

1OZ5181213488ENSG00000184845ENSMUSG00000021478P21728Q61616NM_000794NM_001291801NM_010076NP_000785NP_001278730NP_034206Dopamine receptor D1, also known as DRD1, is a protein that in humans is encoded by the DRD1 gene. Dopamine receptor D1, also known as DRD1, is a protein that in humans is encoded by the DRD1 gene. Based upon Northern blot and in situ hybridization, DRD1 mRNA expression in the central nervous system is highest in the dorsal striatum (caudate and putamen) and ventral striatum (nucleus accumbens and olfactory tubercle). Lower levels of DRD1 mRNA expression occur in the basolateral amygdala, cerebral cortex, septum, thalamus, and hypothalamus. The D1 subtype of the dopamine receptor is the most abundant dopamine receptor in the central nervous system. This G-protein coupled receptor is Gs/a coupled and indirectly activates cyclic AMP-dependent protein kinase, stimulating the neuron. D1 receptors regulate neuronal growth and development, mediate some behavioral responses, and modulate dopamine receptor D2-mediated events. Alternative transcription initiation sites result in two transcript variants of the gene. D1-D2 dopamine receptor heteromer formation is observed. 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). D1 receptor has a high degree of structural homology to another dopamine receptor, D5, and they both bind similar drugs. 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. 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. 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. 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. In 2017, Pfizer made public information about pharmaceutically-acceptable non-catechol selective D1 agonists that are in clinical development. Many typical and atypical antipsychotics are D1 receptor antagonists in addition to D2 receptor antagonists. 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. Dopamine receptor D1 has been shown to interact with: The D1 receptor forms heteromers with the following receptors: dopamine D2 receptor, dopamine D3 receptor, histamine H3 receptor, μ opioid receptor, NMDA receptor, and adenosine A1 receptor.