A dopamine agonist (DA) is a compound that activates

dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic compound, organic chemical of the catecholamine and phenethylamine families. Dopamine const ...

receptors. There are two families of

dopamine receptors Dopamine receptors are a class of G protein-coupled receptors that are prominent in the vertebrate central nervous system (CNS). Dopamine receptors activate different effectors through not only G-protein coupling, but also signaling through diffe ...

, D₂-like and D₁-like, and they are all

G protein-coupled receptors G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...

. D₁- and D₅-receptors belong to the D₁-like family and the D₂-like family includes D₂, D₃ and D₄ receptors. Dopamine agonists are primarily used to treat

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 becom ...

. They are also used, to a far lesser extent, in treating

hyperprolactinemia Hyperprolactinaemia is the presence of abnormally high levels of prolactin in the blood. Normal levels average to about 13 ng/mL in women, and 5 ng/mL in men, with an upper normal limit of serum prolactin levels being 15-25 ng/mL ...

and

restless legs syndrome Restless legs syndrome (RLS), also known as Willis-Ekbom disease (WED), is generally a long-term disorder that causes a strong urge to move one's legs. There is often an unpleasant feeling in the legs that improves somewhat by moving them. This ...

. They are not intended for treatment of

clinical depression Major depressive disorder (MDD), also known as clinical depression, is a mental disorder characterized by at least two weeks of pervasive low mood, low self-esteem, and loss of interest or pleasure in normally enjoyable activities. Introdu ...

, and studies have shown severe detrimental side effects resulting from off-label use of dopamine agonists in treating depression, particularly in their tendency to produce

impulse control disorder Impulse-control disorder (ICD) is a class of psychiatric disorders characterized by impulsivity – failure to resist a temptation, an urge, or an impulse; or having the inability to not speak on a thought. Many psychiatric disorders feature imp ...

s and extreme cases of

withdrawal syndrome Drug withdrawal, drug withdrawal syndrome, or substance withdrawal syndrome, is the group of symptoms that occur upon the abrupt discontinuation or decrease in the intake of pharmaceutical or recreational drugs. In order for the symptoms of wit ...

Medical uses

Parkinson's disease

Dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic compound, organic chemical of the catecholamine and phenethylamine families. Dopamine const ...

agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...

s are mainly used in the treatment of

. The cause of Parkinson's is not fully known but genetic factors, for example specific

genetic mutations In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mit ...

, and environmental triggers have been linked to the disease. In Parkinson's disease

dopaminergic neurons Dopaminergic cell groups, DA cell groups, or dopaminergic nuclei are collections of neurons in the central nervous system that synthesize the neurotransmitter dopamine. In the 1960s, dopaminergic neurons or ''dopamine neurons'' were first ident ...

that produce the

neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell. Neuro ...

in the brain slowly break down and can eventually die. With decreasing levels of dopamine the brain can't function properly and causes abnormal brain activity, which ultimately leads to the symptoms of Parkinson's disease. There are two fundamental ways of treating Parkinson's disease, either by replacing dopamine or mimicking its effect. Dopamine agonists act directly on the dopamine receptors and mimic dopamine's effect. Dopamine agonists have two subclasses:

ergoline Ergoline is a chemical compound whose structural skeleton is contained in a variety of alkaloids, referred to as ergoline derivatives or ergoline alkaloids. Ergoline alkaloids, one being ergine, were initially characterized in ergot. Some of thes ...

and non ergoline agonists. Both subclasses target dopamine D₂-type receptors. Types of ergoline agonists are

cabergoline Cabergoline, sold under the brand name Dostinex among others, is a dopaminergic medication used in the treatment of high prolactin levels, prolactinomas, Parkinson's disease, and for other indications. It is taken by mouth. Cabergoline is an e ...

and

bromocriptine Bromocriptine, originally marketed as Parlodel and subsequently under many brand names, is an ergoline derivative and dopamine agonist that is used in the treatment of pituitary tumors, Parkinson's disease, hyperprolactinaemia, neuroleptic maligna ...

and examples of non-ergoline agonists are

pramipexole Pramipexole, sold under the brand Mirapex among others, is medication used to treat Parkinson's disease (PD) and restless legs syndrome (RLS). In Parkinson's disease it may be used alone or together with levodopa. It is taken by mouth. Pramipex ...

ropinirole Ropinirole, sold under the brand name Requip among others, is a medication used to treat Parkinson's disease (PD) and restless legs syndrome (RLS). In PD the dose needs to be adjusted to the effect and treatment should not be suddenly stopped. ...

and

rotigotine Rotigotine, sold under the brand name Neupro among others, is a dopamine agonist of the non-ergoline class of medications indicated for the treatment of Parkinson's disease and restless legs syndrome. It is formulated as a once-daily transdermal ...

. Ergoline agonists are much less used nowadays because of the risk of

cartilage Cartilage is a resilient and smooth type of connective tissue. In tetrapods, it covers and protects the ends of long bones at the joints as articular cartilage, and is a structural component of many body parts including the rib cage, the neck an ...

formation in heart valves.

Treatment of depression in Parkinson's patients

Depressive symptoms Depression is a mental state of low Mood (psychology), mood and aversion to activity, which affects more than 280 million people of all ages (about 3.5% of the global population). Classified medically as a mental disorder, mental and Abnor ...

and disorders are common in patients with Parkinson's disease and can affect their quality of life. Increased anxiety can accentuate the symptoms of Parkinson's and is therefore essential to treat. Instead of conventional antidepressant medication in treating depression, treatment with dopamine agonists has been suggested. It is mainly thought that dopamine agonists help with treating depressive symptoms and disorders by alleviating motor complications, which is one of the main symptoms of Parkinson's disease. Although preliminary evidence of clinical trials has shown interesting results, further research is crucial to establish the anti-depressive effects of dopamine agonists in treating depressive symptoms and disorders in those with Parkinson's.

Hyperprolactinemia

is a prolactin-inhibiting factor (PIFs) since it lowers the prolactin-releasing factors (PRFs) synthesis and secretion through D₂-like receptors. That is why dopamine agonists are the first-line treatment in

. Ergoline-derived agents,

and

are mostly used in treatment. Research shows that these agents reduce the size of

prolactinoma A prolactinoma is a tumor ( adenoma) of the pituitary gland that produces the hormone prolactin. It is the most common type of functioning pituitary tumor. Symptoms of prolactinoma are due to abnormally high levels of prolactin in the blood (hyp ...

s by suppressing the hypersecretion of

prolactin Prolactin (PRL), also known as lactotropin, is a protein best known for its role in enabling mammals to produce milk. It is influential in over 300 separate processes in various vertebrates, including humans. Prolactin is secreted from the pit ...

resulting in normal

gonad A gonad, sex gland, or reproductive gland is a mixed gland that produces the gametes and sex hormones of an organism. Female reproductive cells are egg cells, and male reproductive cells are sperm. The male gonad, the testicle, produces sper ...

al function.

Restless leg syndrome

Numerous clinical trials have been performed to assess the use of dopamine agonists for the treatment of

restless leg syndrome Restless legs syndrome (RLS), also known as Willis-Ekbom disease (WED), is generally a long-term disorder that causes a strong urge to move one's legs. There is often an unpleasant feeling in the legs that improves somewhat by moving them. This ...

(RLS). RLS is identified by the strong urge to move and is a dopamine-dependent disorder. RLS symptoms decrease with the use of drugs that stimulate dopamine receptors and increase dopamine levels, such as dopamine agonists.

Adverse effects

Side effects

Dopamine agonists are mainly used to treat

Parkinson’s 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 become ...

disease but are also used to treat

and

. The side effects are mainly recorded in treatment for Parkinson’s disease where dopamine agonists are commonly used, especially as first-line treatment with

levodopa -DOPA, also known as levodopa and -3,4-dihydroxyphenylalanine, is an amino acid that is made and used as part of the normal biology of some plants and animals, including humans. Humans, as well as a portion of the other animals that utilize -DOPA ...

. Dopamine agonists are divided into two subgroups or drug classes, first-generation and newer agents. Ergoline derived agonists are the first generation and are not used as much as the newer generation the non-ergoline derived agonists. Ergoline derived agonists are said to be "dirtier" drugs because of their interaction with other receptors than dopamine receptors, therefore they cause more side effects. Ergoline derived agonists are for example

pergolide Pergolide, sold under the brand name Permax and Prascend (veterinary) among others, is an ergoline-based dopamine receptor agonist used in some countries for the treatment of Parkinson's disease. Parkinson's disease is associated with reduced do ...

and

lisuride Lisuride, sold under the brand name Dopergin among others, is a monoaminergic medication of the ergoline class which is used in the treatment of Parkinson's disease, migraine, and high prolactin levels. It is taken by mouth. Side effects of lis ...

. Non-ergoline agonists are

piribedil Piribedil (trade names Pronoran, Trivastal Retard, Trastal, Trivastan, Clarium and others) is an antiparkinsonian agent and piperazine derivative which acts as a D2 and D3 receptor agonist. It also has α2-adrenergic antagonist properties. ...

and

apomorphine Apomorphine, sold under the brand name Apokyn among others, is a type of aporphine having activity as a non- selective dopamine agonist which activates both D2-like and, to a much lesser extent, D1-like receptors. It also acts as an antag ...

. The most common adverse effects are

constipation Constipation is a bowel dysfunction that makes bowel movements infrequent or hard to pass. The stool is often hard and dry. Other symptoms may include abdominal pain, bloating, and feeling as if one has not completely passed the bowel movement ...

nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the ...

and

headache Headache is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of depression in those with severe headaches. Headaches can occur as a result ...

s. Other serious side effects are

hallucination A hallucination is a perception in the absence of an external stimulus that has the qualities of a real perception. Hallucinations are vivid, substantial, and are perceived to be located in external objective space. Hallucination is a combinatio ...

peripheral edema Peripheral edema is edema (accumulation of fluid causing swelling) in tissues perfused by the peripheral vascular system, usually in the lower limbs. In the most dependent parts of the body (those hanging distally), it may be called dependent edem ...

, gastrointestinal ulcers,

pulmonary fibrosis Pulmonary fibrosis is a condition in which the lungs become scarred over time. Symptoms include shortness of breath, a dry cough, feeling tired, weight loss, and nail clubbing. Complications may include pulmonary hypertension, respiratory failu ...

and

psychosis Psychosis is a condition of the mind that results in difficulties determining what is real and what is not real. Symptoms may include delusions and hallucinations, among other features. Additional symptoms are incoherent speech and behavior ...

. Dopamine agonists have been linked to cardiac problems. Side effects such as

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 dias ...

myocardial infarction A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which may ...

, congestive heart failure, cardiac fibrosis,

pericardial effusion A pericardial effusion is an abnormal accumulation of fluid in the pericardial cavity. The pericardium is a two-part membrane surrounding the heart: the outer fibrous connective membrane and an inner two-layered serous membrane. The two layers of t ...

and

tachycardia Tachycardia, also called tachyarrhythmia, is a heart rate that exceeds the normal resting rate. In general, a resting heart rate over 100 beats per minute is accepted as tachycardia in adults. Heart rates above the resting rate may be normal (su ...

. A high risk for

valvular heart disease Valvular heart disease is any cardiovascular disease process involving one or more of the four valves of the heart (the aortic and mitral valves on the left side of heart and the pulmonic and tricuspid valves on the right side of heart). These ...

has been established in association with ergot-derived agonists especially in elderly patients with hypertension.

Somnolence Somnolence (alternatively sleepiness or drowsiness) is a state of strong desire for sleep, or sleeping for unusually long periods (compare hypersomnia). It has distinct meanings and causes. It can refer to the usual state preceding falling asleep ...

and sleep attacks have been reported as an adverse effect that happen to almost 30% of patients using dopamine agonists. Daytime sleepiness,

insomnia Insomnia, also known as sleeplessness, is a sleep disorder in which people have trouble sleeping. They may have difficulty falling asleep, or staying asleep as long as desired. Insomnia is typically followed by daytime sleepiness, low energy, ...

and other sleep disturbances have been reported as well.

Impulse control disorder Impulse-control disorder (ICD) is a class of psychiatric disorders characterized by impulsivity – failure to resist a temptation, an urge, or an impulse; or having the inability to not speak on a thought. Many psychiatric disorders feature imp ...

that is described as gambling, hypersexuality, compulsive shopping and binge eating is one serious adverse effect of dopamine agonists. After long-term use of dopamine agonist a

may occur when discontinuing or during dose reduction. The following side effects are possible: anxiety, panic attacks,

dysphoria Dysphoria (; ) is a profound state of unease or dissatisfaction. It is the semantic opposite of euphoria. In a psychiatric context, dysphoria may accompany depression, anxiety, or agitation. In psychiatry Intense states of distress and unea ...

, depression, agitation, irritability, suicidal ideation, fatigue,

orthostatic hypotension Orthostatic hypotension, also known as postural hypotension, is a medical condition wherein a person's blood pressure drops when standing up or sitting down. Primary orthostatic hypertension is also often referred to as neurogenic orthostatic hyp ...

, nausea, vomiting,

diaphoresis Perspiration, also known as sweating, is the production of fluids secreted by the sweat glands in the skin of mammals. Two types of sweat glands can be found in humans: eccrine glands and apocrine glands. The eccrine sweat glands are distribut ...

, generalised pain, and drug cravings. For some individuals, these withdrawal symptoms are short-lived and make a full recovery, for others a

protracted withdrawal syndrome Post-acute withdrawal syndrome (PAWS) is a hypothesized set of persistent impairments that occur after withdrawal from alcohol, opiates, benzodiazepines, antidepressants, and other substances. Infants born to mothers who used substances of depen ...

may occur with withdrawal symptoms persisting for months or years.

Interactions

Dopamine agonists

interact Advocates for Informed Choice, 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 traits. The organizati ...

with a number of

drug A drug is any chemical substance that causes a change in an organism's physiology or psychology when consumed. Drugs are typically distinguished from food and substances that provide nutritional support. Consumption of drugs can be via insuffla ...

s but there is little evidence that they

with other

drugs. In most cases there is no reason not to co-administer Parkinson's drugs. Although there has been an indication that the use of dopamine agonists with

L-DOPA -DOPA, also known as levodopa and -3,4-dihydroxyphenylalanine, is an amino acid that is made and used as part of the normal biology of some plants and animals, including humans. Humans, as well as a portion of the other animals that utilize -DOPA ...

can cause

therefore it is recommended that either the use of dopamine agonists be discontinued or the dose of

reduced. Since ergot-dopamine

have antihypertensive qualities it is wise to monitor

blood pressure Blood pressure (BP) is the pressure of circulating blood against the walls of blood vessels. Most of this pressure results from the heart pumping blood through the circulatory system. When used without qualification, the term "blood pressure" r ...

when using dopamine agonists with

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 tha ...

drugs to ensure that the patient does not get

. That includes the drug

sildenafil Sildenafil, sold under the brand name Viagra, among others, is a medication used to treat erectile dysfunction and pulmonary arterial hypertension. It is unclear if it is effective for treating sexual dysfunction in women. It is taken by ...

which is commonly used to treat

erectile dysfunction Erectile dysfunction (ED), also called impotence, is the type of sexual dysfunction in which the penis fails to become or stay erect during sexual activity. It is the most common sexual problem in men.Cunningham GR, Rosen RC. Overview of male ...

but also used for pulmonary hypertension. There is evidence that suggests that since ergot dopamine agonists are

metabolized Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...

CYP3A4 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine. It oxidizes small foreign organic molecules (xenobiotics), such as toxins or drugs, so that they can be removed from t ...

enzyme concentration rises with the use of CYP3A4 inhibitors. For example, in one study

was given with a CYP3A4 inhibitor and the AUC (e. Area under the curve) increased 268%.

Ropinirole Ropinirole, sold under the brand name Requip among others, is a medication used to treat Parkinson's disease (PD) and restless legs syndrome (RLS). In PD the dose needs to be adjusted to the effect and treatment should not be suddenly stopped. ...

is a non-ergot derived dopamine

and concomitant use with a CYP1A2 inhibitor can result in a higher concentration of ropinirole. When discontinuing the

CYP1A2 Cytochrome P450 1A2 (abbreviated CYP1A2), a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the human body. In humans, the CYP1A2 enzyme is encoded by the ''CYP1A2'' gene. Function ...

inhibitor, if using both drugs, there is a change that a dose adjustment for ropinirole is needed. There is also evidence the dopamine agonists inhibit various CYP enzymes and therefore they may inhibit the metabolism of certain drugs.

Pharmacology

Ergoline class

Pharmacokinetics of Bromocriptine

The

absorption Absorption may refer to: Chemistry and biology * Absorption (biology), digestion **Absorption (small intestine) *Absorption (chemistry), diffusion of particles of gas or liquid into liquid or solid materials *Absorption (skin), a route by which ...

of the oral dose is approximately 28% however, only 6% reaches the systemic circulation unchanged, due to a substantial first-pass effect.

Bromocriptine Bromocriptine, originally marketed as Parlodel and subsequently under many brand names, is an ergoline derivative and dopamine agonist that is used in the treatment of pituitary tumors, Parkinson's disease, hyperprolactinaemia, neuroleptic maligna ...

reaches mean peak plasma levels in about 1–1.5 hours after a single oral dose. The drug has high

protein binding Plasma protein binding refers to the degree to which medications attach to proteins within the blood. A drug's efficiency may be affected by the degree to which it binds. The less bound a drug is, the more efficiently it can traverse or diffuse th ...

, ranging from 90-96% bound to serum

albumin Albumin is a family of globular proteins, the most common of which are the serum albumins. All the proteins of the albumin family are water-soluble, moderately soluble in concentrated salt solutions, and experience heat denaturation. Albumins ...

. Bromocriptine is

and excreted primarily in the

feces Feces ( or faeces), known colloquially and in slang as poo and poop, are the solid or semi-solid remains of food that was not digested in the small intestine, and has been broken down by bacteria in the large intestine. Feces contain a relati ...

via biliary secretion. Metabolites and parent drugs are mostly

excreted Excretion is a process in which metabolic waste is eliminated from an organism. In vertebrates this is primarily carried out by the lungs, kidneys, and skin. This is in contrast with secretion, where the substance may have specific tasks after lea ...

via the

liver The liver is a major Organ (anatomy), organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of proteins and biochemicals necessary for ...

, but also 6% via the

kidney The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; blood ...

. It has a

half-life Half-life (symbol ) is the time required for a quantity (of substance) to reduce to half of its initial value. The term is commonly used in nuclear physics to describe how quickly unstable atoms undergo radioactive decay or how long stable ato ...

of 2–8 hours.

Pharmacokinetics of Pergolide

Pergolide Pergolide, sold under the brand name Permax and Prascend (veterinary) among others, is an ergoline-based dopamine receptor agonist used in some countries for the treatment of Parkinson's disease. Parkinson's disease is associated with reduced do ...

has a long half-life of about 27 hours and reaches a mean peak plasma level in about 2–3 hours after a single oral dose. The protein binding is 90% and the drug is mainly metabolized in the liver by CYP3A4 and

CYP2D6 Cytochrome P450 2D6 (CYP2D6) is an enzyme that in humans is encoded by the ''CYP2D6'' gene. ''CYP2D6'' is primarily expressed in the liver. It is also highly expressed in areas of the central nervous system, including the substantia nigra. CYP2D ...

. The major route of excretion is through the kidneys.

Non-Ergoline class

Pharmacokinetics of Pramipexole

Pramipexole Pramipexole, sold under the brand Mirapex among others, is medication used to treat Parkinson's disease (PD) and restless legs syndrome (RLS). In Parkinson's disease it may be used alone or together with levodopa. It is taken by mouth. Pramipex ...

reaches maximum plasma concentration 1–3 hours post-dose. It is about 15% bound to plasma proteins and the metabolism is minimal. Pramipexole has a long half-life, around 27 hours. The drug is mostly excreted in the urine, around 90%, but also in feces.

Pharmacokinetics of Ropinirole

is rapidly absorbed after a single oral dose, reaching plasma concentration in approximately 1–2 hours. The half-life is around 5–6 hours. Ropinirole is heavily metabolized by the liver and

in vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology an ...

studies show that the

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...

involved in the metabolism of ropinirole is

Pharmacokinetics of Rotigotine

Since

is a

transdermal patch A transdermal patch is a medicated adhesive patch that is placed on the skin to deliver a specific dose of medication through the skin and into the bloodstream. An advantage of a transdermal drug delivery route over other types of medicat ...

it provides continuous drug delivery over 24 hours. It has a half-life of 3 hours and the protein binding is around 92% in vitro and 89.5%

in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...

. Rotigotine is extensively and rapidly metabolized in the liver and by the CYP enzymes. The drug is mostly excreted in urine (71%), but also in feces (23%).

Mechanism of action

The dopamine receptors are 7-

transmembrane A transmembrane protein (TP) is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequentl ...

domains and are members of the G protein-coupled receptors (GPCR) superfamily. Dopamine receptors have five subtypes, D₁ through D₅, the subtypes can be divided into two subclasses due to their mechanism of action on adenylate cyclase enzyme, D₁-like receptors (D₁ and D₅) and D₂-like receptors (D₂, D₃ and D₄). D₁-like receptors are primarily coupled to Gα_s/olf proteins and activates adenylate cyclase which increases intracellular levels of

cAMP Camp may refer to: Outdoor accommodation and recreation * Campsite or campground, a recreational outdoor sleeping and eating site * a temporary settlement for nomads * Camp, a term used in New England, Northern Ontario and New Brunswick to descri ...

, they also activate the G_βγ complex and the N-type Ca²⁺ channel. D₂-like receptors decrease intracellular levels of the second messenger cAMP by inhibiting adenylate cyclase.

Bromocriptine

is an ergot derivative, semi-synthetic. Bromocriptine is a D₂ receptor agonist and D₁ receptor antagonist with a binding affinity to D₂ receptors of anterior pituitary cells, exclusively on lactotrophs. Bromocriptine stimulates Na⁺, K⁺-ATPase activity and/or cytosolic Ca²⁺ elevation and therefore reduction of prolactin which leads to no production of cAMP.

Pramipexol

Pramipexol is a highly active non-ergot D₂-like receptor agonist with a higher binding affinity to D₃ receptors rather than D₂ or D₄ receptors. The mechanism of action of pramipexole is mostly unknown, it is thought to be involved in the activation of dopamine receptors in the area of the brain where the striatum and the substantia nigra is located. This stimulation of dopamine receptors in the striatum may lead to the better movement performance.

Structure–activity relationship

When dealing with agonists it can be extremely complex to confirm relationships between structure and biological activity. Agonists generate responses from living tissues. Therefore, their activity depends both on their

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 pragmatic clinical trial#Efficacy versu ...

to activate receptors and their affinity to bind to receptors.

Crossing the blood brain barrier

Many molecules are unable to cross the

blood brain barrier Blood is a body fluid in the circulatory system of humans and other vertebrates that delivers necessary substances such as nutrients and oxygen to the Cell (biology), cells, and transports Metabolic waste, metabolic waste products away from th ...

(BBB). Molecules must be small,

non-polar In chemistry, polarity is a separation of electric charge leading to a molecule or its chemical groups having an electric dipole moment, with a negatively charged end and a positively charged end. Polar molecules must contain one or more pola ...

and

lipophilic Lipophilicity (from Greek λίπος "fat" and φίλος "friendly"), refers to the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. Such non-polar solvents are themselves lipop ...

to cross over. If compounds do not possess these qualities they must have a specific transporter that can transport them over the BBB. Dopamine cannot diffuse across the BBB because of the

catechol Catechol ( or ), also known as pyrocatechol or 1,2-dihydroxybenzene, is a toxic organic compound with the molecular formula . It is the ''ortho'' isomer of the three isomeric benzenediols. This colorless compound occurs naturally in trace amoun ...

group, it is too polar and therefore unable to enter the brain. The catechol group is a dihydroxy

benzene Benzene is an organic chemical compound with the molecular formula C6H6. The benzene molecule is composed of six carbon atoms joined in a planar ring with one hydrogen atom attached to each. Because it contains only carbon and hydrogen atoms, ...

ring. The synthesis of dopamine consists of three stages. The synthesis process starts with an amino acid, called

L-Tyrosine -Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a non-essential amino acid with a polar side group. The word "tyrosine" is from the Gr ...

. In the second stage

Levodopa -DOPA, also known as levodopa and -3,4-dihydroxyphenylalanine, is an amino acid that is made and used as part of the normal biology of some plants and animals, including humans. Humans, as well as a portion of the other animals that utilize -DOPA ...

(L-dopa) is formed by adding a phenol group to the benzene ring of L-Tyrosine. The formation of L-dopa from L-tyrosine is catalyzed by the enzyme tyrosine hydroxylase. The third stage is the formation of dopamine by removing the carboxylic acid group from L-dopa, catalysed by the enzyme dopa decarboxylase. Levodopa is also too polar to cross the blood brain barrier but it happens to be an amino acid so it has a specialized transporter called L-type amino acid transporter or LAT-1 that helps it diffuse through the barrier.

Dopamine

When dopamine interacts with ATP, which is a component of some dopamine receptors, it has a significant preference for a trans-conformation of the dopamine molecule. The dopamine-ATP complex is stabilised by

hydrogen bond In chemistry, a hydrogen bond (or H-bond) is a primarily electrostatic force of attraction between a hydrogen (H) atom which is covalently bound to a more electronegative "donor" atom or group (Dn), and another electronegative atom bearing a ...

ing between catechol hydroxyls and purine nitrogens and by

electrostatic interactions Electrostatics is a branch of physics that studies electric charges at Rest (physics), rest (static electricity). Since classical antiquity, classical times, it has been known that some materials, such as amber, attract lightweight particles af ...

between the protonated

ammonium The ammonium cation is a positively-charged polyatomic ion with the chemical formula or . It is formed by the protonation of ammonia (). Ammonium is also a general name for positively charged or protonated substituted amines and quaternary a ...

group of dopamine and a negative

phosphate In chemistry, a phosphate is an anion, salt, functional group or ester derived from a phosphoric acid. It most commonly means orthophosphate, a derivative of orthophosphoric acid . The phosphate or orthophosphate ion is derived from phospho ...

group. Two conformers of dopamine have been identified as alpha- and beta-conformers in which the catechol ring is coplanar with the plane of the ethylamine side chain. They are substantial in agonist-receptor interactions.

Ergoline derivatives

Central dopaminergic agonist properties of semisynthetic

derivatives lergotrile,

and

have been established. Some studies suggest that ergot alkaloids have the properties of mixed agonist-antagonist with regards to certain presynaptic and postsynaptic receptors. N-n-

Propyl In organic chemistry, propyl is a three-carbon alkyl substituent with chemical formula for the linear form. This substituent form is obtained by removing one hydrogen atom attached to the terminal carbon of propane. A propyl substituent is often ...

groups (chemical formula: –CH₂CH₂CH₃) frequently enhance dopamine agonist effects in the ergoline derivatives. Bromocriptine

The (+)-

enantiomer In chemistry, an enantiomer ( /ɪˈnænti.əmər, ɛ-, -oʊ-/ ''ih-NAN-tee-ə-mər''; from Ancient Greek ἐνάντιος ''(enántios)'' 'opposite', and μέρος ''(méros)'' 'part') – also called optical isomer, antipode, or optical ant ...

displays notably diminished activity whereas the (-)-enantiomer possess potent dopamine agonist properties.

''Bromocriptine''

has an ergot alkaloid structure. Ergot alkaloids are divided into 2 groups; amino acid ergot alkaloids and amine ergot alkaloids, bromocriptine is part of the former group. It contains a

bromine Bromine is a chemical element with the symbol Br and atomic number 35. It is the third-lightest element in group 17 of the periodic table (halogens) and is a volatile red-brown liquid at room temperature that evaporates readily to form a simila ...

halogen The halogens () are a group in the periodic table consisting of five or six chemically related elements: fluorine (F), chlorine (Cl), bromine (Br), iodine (I), astatine (At), and tennessine (Ts). In the modern IUPAC nomenclature, this group is ...

on the ergot structure which increases the affinity for the D₂-receptor but often reduces the efficacy. The similarity between the dopamine structure and the ergoline ring in bromocriptine is likely the cause for its action on the dopamine receptors. It has shown to have equal affinity for D₂- and D₃-receptor and much lower affinity for D₁-receptor. Apomorphine

Non-ergoline derivatives

Non-ergoline dopamine receptor agonists have higher binding affinity to dopamine D₃-receptors than dopamine D₂-receptors. This binding affinity is related to D₂ and D₃ receptor homology, the homology between them has a high degree of sequence and is closest in their transmembrane domains, were they share around 75% of the amino acid. Rotigotine

''Apomorphine''

Apomorphine Apomorphine, sold under the brand name Apokyn among others, is a type of aporphine having activity as a non- selective dopamine agonist which activates both D2-like and, to a much lesser extent, D1-like receptors. It also acts as an antag ...

has a

element and belongs to a class called β-phenylethylamines and its main components are similar to the dopamine structure. The effect that apomorphine has on the dopamine receptors can also be linked to the similarities between its structure and dopamine. It is a

chiral Chirality is a property of asymmetry important in several branches of science. The word ''chirality'' is derived from the Greek (''kheir''), "hand", a familiar chiral object. An object or a system is ''chiral'' if it is distinguishable from ...

molecule and thus can be acquired in both the R and S form, the R form is the one that is used in therapy. When apomorphine interacts with the dopamine receptor, or the ATP on the receptor, the catechol and nitrogen are important to stabilize the structure with hydrogen bonding. The position of the hydroxyl groups is also important and monohydroxy derivatives have been found to be less potent than the dihydroxy groups. There are a number of stability concerns with apomorphine such as oxidation and racemization.

''Rotigotine''

Rotigotine Rotigotine, sold under the brand name Neupro among others, is a dopamine agonist of the non-ergoline class of medications indicated for the treatment of Parkinson's disease and restless legs syndrome. It is formulated as a once-daily transdermal ...

is a phenolic amine and thus has poor oral bioavailability and fast clearance from the body. Therefore, it has been formulated as a

, first and foremost to prevent

first pass metabolism The first pass effect (also known as first-pass metabolism or presystemic metabolism) is a phenomenon of drug metabolism whereby the concentration of a drug, specifically when administered orally, is greatly reduced before it reaches the system ...

in the liver.

Members

Examples of dopamine agonists include:

Partial agonist

Aripiprazole Aripiprazole, sold under the brand names Abilify and Aristada among others, is an atypical antipsychotic. It is primarily used in the treatment of schizophrenia and bipolar disorder. Other uses include as an add-on treatment in major depressiv ...

(Partial agonist of the D₂ family receptors - Trade name "Abilify" in the United States; atypical

antipsychotic Antipsychotics, also known as neuroleptics, are a class of Psychiatric medication, psychotropic medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), principally in schizophrenia but ...

) *

Phencyclidine Phencyclidine or phenylcyclohexyl piperidine (PCP), also known as angel dust among other names, is a dissociative anesthetic mainly used recreationally for its significant mind-altering effects. PCP may cause hallucinations, distorted perceptio ...

(a.k.a. PCP; partial agonist. Psychoactivity mainly due to NMDA antagonism) * Quinpirole (Partial agonist of the D₂ and D₃ family of receptors) *

Salvinorin A Salvinorin A is the main active psychotropic molecule in '' Salvia divinorum''. Salvinorin A is considered a dissociative hallucinogen. It is structurally distinct from other naturally occurring hallucinogens (such as DMT, psilocybin, and ...

(chief active constituent of the psychedelic herb salvia divinorum, the psychoactivity of which is mainly due to Kappa-opioid receptor agonism; partial agonist at the D₂ with an

Intrinsic activity Intrinsic activity (IA) and efficacy refer to the relative ability of a drug-receptor complex to produce a maximum functional response. This must be distinguished from the affinity, which is a measure of the ability of the drug to bind to its mol ...

of 40-60%, binding affinity of K_i=5-10nM and EC₅₀=50-90nM)

Agonists of full/unknown efficacy

(Apokyn – used to treat

Restless leg syndrome Restless legs syndrome (RLS), also known as Willis-Ekbom disease (WED), is generally a long-term disorder that causes a strong urge to move one's legs. There is often an unpleasant feeling in the legs that improves somewhat by moving them. This ...

) – biased at the D1 receptor. *

(Parlodel – used to treat PD/ RLS) *

Cabergoline Cabergoline, sold under the brand name Dostinex among others, is a dopaminergic medication used in the treatment of high prolactin levels, prolactinomas, Parkinson's disease, and for other indications. It is taken by mouth. Cabergoline is an e ...

(Dostinex – used to treat PD/RLS) * Ciladopa (used to treat PD/RLS) *

Dihydrexidine Dihydrexidine (DAR-0100) is a moderately selective full agonist at the dopamine D1 and D5 receptors. It has approximately 10-fold selectivity for D1 and D5 over the D2 receptor. Although dihydrexidine has some affinity for the D2 receptor, ...

(used to treat PD/RLS) * Dinapsoline (used to treat PD/RLS) *

Doxanthrine Doxanthrine is a synthetic compound which is a potent and selective full agonist for the dopamine D1 receptor. Doxanthrine has been shown to be orally active in producing contralateral rotation in the 6-hydroxydopamine rat model of Parkin ...

(used to treat PD/RLS) * Epicriptine (used to treat PD/RLS) *

Lisuride Lisuride, sold under the brand name Dopergin among others, is a monoaminergic medication of the ergoline class which is used in the treatment of Parkinson's disease, migraine, and high prolactin levels. It is taken by mouth. Side effects of lis ...

(used to treat PD/RLS) *

(used to treat PD/RLS) – previously available as Permax, but removed from the market in the USA on March 29, 2007. *

Piribedil Piribedil (trade names Pronoran, Trivastal Retard, Trastal, Trivastan, Clarium and others) is an antiparkinsonian agent and piperazine derivative which acts as a D2 and D3 receptor agonist. It also has α2-adrenergic antagonist properties. ...

(Pronoran and Trivastal – used to treat PD/RLS) *

(Mirapex and Sifrol – used to treat PD/RLS) *

Propylnorapomorphine N-n-Propylnorapomorphine (NPA) is an aporphine derivative dopamine agonist closely related to apomorphine. In rodents it has been shown to produce hyperactivity, stereotypy, hypothermia, antinociception, and penile erection, among other effects. N ...

(used to treat PD/RLS) *

Quinagolide Quinagolide (, ), sold under the brand name Norprolac, is a selective dopamine D2 receptor agonist which is used to reduce elevated levels of prolactin (hyperprolactinemia). It has also been found to be effective in the treatment of breast pa ...

(Norprolac – used to treat PD/RLS) *

(Requip – used to treat PD/RLS) *

(Neupro – used to treat PD/RLS) *

Roxindole Roxindole (EMD-49,980) is a dopaminergic and serotonergic drug which was originally developed by Merck KGaA for the treatment of schizophrenia. In clinical trials its antipsychotic efficacy was only modest but it was unexpectedly found to produc ...

(used to treat PD/RLS) * Sumanirole (used to treat PD/RLS) Some, such as

fenoldopam Fenoldopam mesylate (Corlopam) is a drug and synthetic benzazepine derivative which acts as a selective D1 receptor partial agonist. Fenoldopam is used as an antihypertensive agent. It was approved by the Food and Drug Administration (FDA) in ...

, are selective for

dopamine receptor D1 Dopamine receptor D1, 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 do ...

Related class of drugs: Indirect agonists

There are two classes of drugs that act as

indirect agonist In pharmacology, an indirect agonist or indirect-acting agonist is a substance that enhances the release or action of an endogenous neurotransmitter but has no specific agonist activity at the neurotransmitter receptor itself. Indirect agonists ...

s of dopamine receptors:

dopamine reuptake inhibitor A dopamine reuptake inhibitor (DRI) is a class of drug which acts as a reuptake inhibitor of the monoamine neurotransmitter dopamine by blocking the action of the dopamine transporter (DAT). Reuptake inhibition is achieved when extracellular dopa ...

s and

dopamine releasing agent A dopamine releasing agent (DRA) is a type of drug which induces the release of dopamine in the body and/or brain. No selective DRAs are currently known. Many releasing agents of both dopamine and norepinephrine ( norepinephrine–dopamine releas ...

s. These are not considered dopamine agonists, since they have no specific agonist activity at dopamine

receptors Receptor may refer to: *Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a n ...

, but they are nonetheless related. Indirect agonists are prescribed for a wider range of conditions than standard dopamine agonists. The most commonly prescribed indirect agonists of dopamine receptors include: *

Amphetamine Amphetamine (contracted from alpha- methylphenethylamine) is a strong central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, and obesity. It is also commonly used ...

and/or

dextroamphetamine Dextroamphetamine is a central nervous system (CNS) stimulant and an amphetamine enantiomer that is prescribed for the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. It is also used as an athletic performance an ...

(used to treat

ADHD Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by excessive amounts of inattention, hyperactivity, and impulsivity that are pervasive, impairing in multiple contexts, and otherwise age-inapp ...

narcolepsy Narcolepsy is a long-term neurological disorder that involves a decreased ability to regulate sleep–wake cycles. Symptoms often include periods of excessive daytime sleepiness and brief involuntary sleep episodes. About 70% of those affec ...

, and

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 we ...

) *

Bupropion Bupropion, sold under the brand names Wellbutrin and Zyban among others, is an atypical antidepressant primarily used to treat major depressive disorder and to support smoking cessation. It is also popular as an add-on medication in the case ...

(used to facilitate

smoking cessation Smoking cessation, usually called quitting smoking or stopping smoking, is the process of discontinuing tobacco smoking. Tobacco smoke contains nicotine, which is addictive and can cause dependence. As a result, nicotine withdrawal often make ...

and treat

nicotine addiction Nicotine is a naturally produced alkaloid in the nightshade family of plants (most predominantly in tobacco and ''Duboisia hopwoodii'') and is widely used recreationally as a stimulant and anxiolytic. As a pharmaceutical drug, it is used for ...

and

) *

Lisdexamfetamine Lisdexamfetamine, sold under the brand name Vyvanse among others, is a stimulant medication that is mainly used to treat attention deficit hyperactivity disorder (ADHD) in people over the age of five as well as moderate-to-severe binge eating ...

(used to treat ADHD and

binge eating disorder Binge eating disorder (BED) is an eating disorder characterized by frequent and recurrent binge eating episodes with associated negative psychological and social problems, but without the compensatory behaviors common to bulimia nervosa, OSFED, o ...

) *

Methylphenidate Methylphenidate, sold under the brand names Ritalin and Concerta among others, is the most widely prescribed central nervous system (CNS) stimulant medication used to treat attention deficit hyperactivity disorder (ADHD) and, to a lesser extent, ...

dexmethylphenidate Dexmethylphenidate, sold under the brand name Focalin among others, is a strong central nervous system (CNS) stimulant medication used to treat attention deficit hyperactivity disorder (ADHD) in those over the age of five years. If no benefit i ...

(used to treat ADHD and

) Other examples include: *

Cathinone Cathinone (also known as benzoylethanamine, or β-keto-amphetamine) is a monoamine alkaloid found in the shrub '' Catha edulis'' (khat) and is chemically similar to ephedrine, cathine, methcathinone and other amphetamines. It is probably the m ...

Cocaine Cocaine (from , from , ultimately from Quechuan languages, Quechua: ''kúka'') is a central nervous system (CNS) stimulant mainly recreational drug use, used recreationally for its euphoria, euphoric effects. It is primarily obtained from t ...

(

anesthetic An anesthetic (American English) or anaesthetic (British English; see spelling differences) is a drug used to induce anesthesia ⁠— ⁠in other words, to result in a temporary loss of sensation or awareness. They may be divided into two ...

with no medical uses as a central nervous system stimulant) *

Methamphetamine Methamphetamine (contracted from ) is a potent central nervous system (CNS) stimulant that is mainly used as a recreational drug and less commonly as a second-line treatment for attention deficit hyperactivity disorder and obesity. Methamph ...

(used in rare circumstances to treat ADHD and

) *

Phenethylamine Phenethylamine (PEA) is an organic compound, natural monoamine alkaloid, and trace amine, which acts as a central nervous system stimulant in humans. In the brain, phenethylamine regulates monoamine neurotransmission by binding to trace amin ...

(endogenous

trace amine Trace amines are an endogenous group of trace amine-associated receptor 1 (TAAR1) agonists – and hence, monoaminergic neuromodulators – that are structurally and metabolically related to classical monoamine neurotransmitters. Compared to the ...

) * ''p''-Tyramine (endogenous

)

History

Since the late 1960

(L-DOPA) has been used to treat

disease but there has always been a debate whether the treatment is worth the

side effects In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...

. Around 1970 clinicians started using the dopamine agonist

alongside

to minimize the side effects caused by L-DOPA, the dopamine agonists bind to the dopamine receptor in the absence of dopamine. Apomorphine had limited use since it had considerable side effects and difficulty with administration. In 1974

was use widely after clinicians discovered its benefits in treating

Parkinsons 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 become ...

. When using the two

classes together there is a possibility to reduce the amount of

by 20-30% and thus keeping the fluctuating motor responses to a minimum. Dopamine agonists are often used in younger people as

monotherapy Combination therapy or polytherapy is therapy that uses more than one medication or modality. Typically, the term refers to using multiple therapies to treat a ''single'' disease, and often all the therapies are pharmaceutical (although it can also ...

and as initial therapy instead of L-DOPA. Although it is important to know that there is a correlation between the two drugs, if l-DOPA doesn't work dopamine agonists are also ineffective. The early dopamine agonists, such as bromocriptine, were ergot derived and activated the D₂-receptor. They induced major side effects such as fibrosis of cardiac valves. It is considered that the reason they induced such side effects is that they activate many types of receptors. Because of the major adverse effects of ergot derived dopamine agonists they are generally not used anymore and were mostly abandoned in favor of non-ergot agonists such as

and

. They do not induce as serious side effects although common side effects are

edema Edema, also spelled oedema, and also known as fluid retention, dropsy, hydropsy and swelling, is the build-up of fluid in the body's Tissue (biology), tissue. Most commonly, the legs or arms are affected. Symptoms may include skin which feels t ...

and

. Patients have also shown impaired impulse control such as

overspending Overspending is spending more money than one can afford. It is a common problem when easy credit is available. The term overspending is also used for investment projects when payments exceed actual calculated cost. Causes Some overspending is a f ...

hypersexuality Hypersexuality is extremely frequent or suddenly increased libido. It is controversial whether it should be included as a clinical diagnosis used by mental healthcare professionals. Nymphomania and satyriasis were terms previously used for the c ...

and

gambling Gambling (also known as betting or gaming) is the wagering of something of value ("the stakes") on a random event with the intent of winning something else of value, where instances of strategy are discounted. Gambling thus requires three el ...

References

External links

* {{Euphoriants