Dopamine receptor D
1, also known as DRD1. It is one of the two types of D1-like receptor family - receptors D1 and D5. It is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
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
The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...
.
Northern blot
The northern blot, or RNA blot,Gilbert, S. F. (2000) Developmental Biology, 6th Ed. Sunderland MA, Sinauer Associates. is a technique used in molecular biology research to study gene expression by detection of RNA (or isolated mRNA) in a sampl ...
and
in situ hybridization
''In situ'' hybridization (ISH) is a type of hybridization that uses a labeled complementary DNA, RNA or modified nucleic acids strand (i.e., probe) to localize a specific DNA or RNA sequence in a portion or section of tissue (''in situ'') or ...
show that the
mRNA expression of DRD1 is highest in the
dorsal striatum
The striatum, or corpus striatum (also called the striate nucleus), is a nucleus (a cluster of neurons) in the subcortical basal ganglia of the forebrain. The striatum is a critical component of the motor and reward systems; receives glutamat ...
(
caudate and
putamen) and
ventral striatum
The striatum, or corpus striatum (also called the striate nucleus), is a nucleus (a cluster of neurons) in the subcortical basal ganglia of the forebrain. The striatum is a critical component of the motor and reward systems; receives glutam ...
(
nucleus accumbens
The nucleus accumbens (NAc or NAcc; also known as the accumbens nucleus, or formerly as the ''nucleus accumbens septi'', Latin for "nucleus adjacent to the septum") is a region in the basal forebrain rostral to the preoptic area of the hyp ...
and
olfactory tubercle
The olfactory tubercle (OT), also known as the tuberculum olfactorium, is a multi-sensory processing center that is contained within the olfactory cortex and ventral striatum and plays a role in reward cognition. The OT has also been shown to ...
).
Lower levels occur in the
basolateral amygdala
The basolateral amygdala, or basolateral complex, consists of the lateral, basal and accessory-basal nuclei of the amygdala. The lateral nuclei receives the majority of sensory information, which arrives directly from the temporal lobe structures, ...
,
cerebral cortex
The cerebral cortex, also known as the cerebral mantle, is the outer layer of neural tissue of the cerebrum of the brain in humans and other mammals. The cerebral cortex mostly consists of the six-layered neocortex, with just 10% consisting o ...
,
septum,
thalamus
The thalamus (from Greek θάλαμος, "chamber") is a large mass of gray matter located in the dorsal part of the diencephalon (a division of the forebrain). Nerve fibers project out of the thalamus to the cerebral cortex in all direct ...
, and
hypothalamus
The hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamus ...
.
Function
D1 receptors regulate the
memory
Memory is the faculty of the mind by which data or information is encoded, stored, and retrieved when needed. It is the retention of information over time for the purpose of influencing future action. If past events could not be remember ...
,
learning
Learning is the process of acquiring new understanding, knowledge, behaviors, skills, values, attitudes, and preferences. The ability to learn is possessed by humans, animals, and some machines; there is also evidence for some kind of lea ...
, and the growth of
neurons
A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa ...
, 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
Addiction is a neuropsychological disorder characterized by a persistent and intense urge to engage in certain behaviors, one of which is the usage of a drug, despite substantial harm and other negative consequences. Repetitive drug use o ...
by facilitating the
gene expression changes that occur in the
nucleus accumbens
The nucleus accumbens (NAc or NAcc; also known as the accumbens nucleus, or formerly as the ''nucleus accumbens septi'', Latin for "nucleus adjacent to the septum") is a region in the basal forebrain rostral to the preoptic area of the hyp ...
during addiction.
They are
Gs/a coupled and can stimulate neurons by indirectly activating
cyclic AMP-dependent protein kinase
In cell biology, protein kinase A (PKA) is a family of enzymes whose activity is dependent on cellular levels of cyclic AMP (cAMP). PKA is also known as cAMP-dependent protein kinase (). PKA has several functions in the cell, including regulati ...
.
Production
The DRD1 gene expresses primarily in the
caudate putamen in humans, and in the
caudate putamen, the
nucleus accumbens
The nucleus accumbens (NAc or NAcc; also known as the accumbens nucleus, or formerly as the ''nucleus accumbens septi'', Latin for "nucleus adjacent to the septum") is a region in the basal forebrain rostral to the preoptic area of the hyp ...
and the
olfactory tubercle
The olfactory tubercle (OT), also known as the tuberculum olfactorium, is a multi-sensory processing center that is contained within the olfactory cortex and ventral striatum and plays a role in reward cognition. The OT has also been shown to ...
in mouse. Gene expression patterns from the
Allen Brain Atlas
The Allen Mouse and Human Brain Atlases are projects within the Allen Institute for Brain Science which seek to combine genomics with neuroanatomy by creating gene expression maps for the mouse and human brain. They were initiated in September 2 ...
es in mouse and human can be foun
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,
D5, 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
D2-like receptor agonists.
Fenoldopam is a selective D
1 receptor
partial agonist
In pharmacology, partial agonists are drugs that bind to and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist. They may also be considered ligands which display both agonistic and antagonis ...
that does not cross the
blood-brain-barrier and is used
intravenous
Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrie ...
ly in the treatment of
hypertension
Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms. Long-term high b ...
.
Dihydrexidine and
adrogolide
A-86929 is a synthetic compound that acts as a selective dopamine receptor D1 agonist. It was developed as a possible treatment for Parkinson's disease, as well as for other applications such as treatment of cocaine addiction, but while it had re ...
(ABT-431) (a
prodrug
A prodrug is a medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be used to improve how the dru ...
of
A-86929
A-86929 is a synthetic compound that acts as a selective dopamine receptor D1 agonist. It was developed as a possible treatment for Parkinson's disease, as well as for other applications such as treatment of cocaine addiction, but while it had re ...
with improved
bioavailability) are the only selective, centrally active
D1-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
Hypotension is low blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood. Blood pressure is indicated by two numbers, the systolic blood pressure (the top number) and the di ...
, 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 D1 receptor agonists
* Dihydrexidine derivatives
**
A-86929
A-86929 is a synthetic compound that acts as a selective dopamine receptor D1 agonist. It was developed as a possible treatment for Parkinson's disease, as well as for other applications such as treatment of cocaine addiction, but while it had re ...
- 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
Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms beco ...
.
Although
dihydrexidine has significant D
2 properties, it is highly biased at D
2 receptors and was used for the first demonstration of
functional selectivity
Functional selectivity (or “agonist trafficking”, “biased agonism”, “biased signaling”, "ligand bias" and “differential engagement”) is the ligand-dependent selectivity for certain signal transduction pathways relative to a referen ...
with dopamine receptors.
**
Dinapsoline
Dinapsoline is a drug developed for the treatment of Parkinson's disease, that acts as a binding selectivity, selective full agonist at the dopamine D1 receptor, D1 Receptor (biochemistry), receptor.
References
D1-receptor agonists
Ca ...
- 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
Antihypertensives are a class of drugs that are used to treat hypertension (high blood pressure). Antihypertensive therapy seeks to prevent the complications of high blood pressure, such as stroke and myocardial infarction. Evidence suggests th ...
**
6-Br-APB - 90-fold selectivity for D
1 over D
2
* 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 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''soquinoline: 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.
Antagonists
Many
typical
Typical may refer to:
* ''Typical'' (album), Peter Hammill
* "Typical" (song), song by MuteMath
*"Typical", song by Frazier Chorus from ''Sue'', 1987
*''Typical'', story collection by Padgett Powell
Padgett Powell (born April 25, 1952 in Gaine ...
and
atypical antipsychotics are D
1 receptor antagonists in addition to D
2 receptor antagonists. 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
Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social w ...
,
cocaine abuse,
obesity
Obesity is a medical condition, sometimes considered a disease, in which excess body fat has accumulated to such an extent that it may negatively affect health. People are classified as obese when their body mass index (BMI)—a person's ...
,
pathological gambling
Problem gambling or ludomania is repetitive gambling behavior despite harm and negative consequences. Problem gambling may be diagnosed as a mental disorder according to ''DSM-5'' if certain diagnostic criteria are met. Pathological gambling is ...
, and
Tourette's syndrome, with
efficacy
Efficacy is the ability to perform a task to a satisfactory or expected degree. The word comes from the same roots as ''effectiveness'', and it has often been used synonymously, although in pharmacology a distinction is now often made between ...
in some of these conditions seen. The drug produced mild-to-moderate, reversible
depression and
anxiety
Anxiety is an emotion which is characterized by an unpleasant state of inner turmoil and includes feelings of dread over anticipated events. Anxiety is different than fear in that the former is defined as the anticipation of a future threat wh ...
in clinical studies however and has yet to complete development for any indication.
List of D1 receptor antagonists
* Benzazepine derivatives
**
SCH-23,390 - 100-fold selectivity for D
1 over D
5
**
Ecopipam (SCH-39,166) - a selective D
1/D
5 antagonist that was being developed as an
anti-obesity medication
Anti-obesity medication or weight loss medications are pharmacological agents that reduce or control weight. These medications alter one of the fundamental processes of the human body, weight regulation, by altering either appetite, or absor ...
but was discontinued
* Antipsychotics
**
Asenapine - It has higher D1 receptor affinity compared to other antipsychotics
Modulators
* DETQ − PAM
*
LY-3154207 – potent and subtype selective PAM, in phase 2 studies for Lewy body dementia.
Protein–protein interactions
Dopamine receptor D
1 has been shown to
interact
Advocates for Informed Choice, doing business as, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex trai ...
with:
*
COPG2,
[
* ]COPG
Coatomer subunit gamma is a protein that in humans is encoded by the ''COPG'' gene. It is one of seven proteins in the COPI coatomer complex that coats vesicles as they bud from the Golgi complex.
Interactions
COPG has been shown to interact wit ...
, and
* DNAJC14.
Receptor oligomers
The D1 receptor forms heteromers with the following receptors: dopamine D2 receptor, dopamine D3 receptor, histamine H3 receptor, μ opioid receptor, NMDA receptor
The ''N''-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other two being AMPA and ...
, and adenosine A1 receptor.
Dopamine D1 receptor hetero-oligomers
/ref>
* D1–D2 receptor complex
* D1− H3− NMDAR receptor complex − a target to prevent neurodegeneration
* D1– D3 receptor complex
* D1– NMDAR receptor complex
* D1– A1 receptor complex
Structure
Several CryoEM
Cryogenic electron microscopy (cryo-EM) is a cryomicroscopy technique applied on samples cooled to cryogenic temperatures. For biological specimens, the structure is preserved by embedding in an environment of vitreous ice. An aqueous sample so ...
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.
See also
* Dopamine receptor
References
External links
*
*
{{Dopaminergics
Dopamine receptors