Dopamine agonist

Short description: Compound that activates dopamine receptors

Not to be confused with dopamine antagonist.

Dopamine agonist

Drug class

The skeletal structure of dopamine

Class identifiers
Use| Parkinson's disease, hyperprolactinemia, restless legs syndrome
ATC code| N04BC
Biological target| Dopamine receptors
External links
MeSH| D010300

A dopamine agonist is a compound that activates dopamine D2 receptors and belong to one of two different subclasses: ergoline and non-ergoline. Examples of ergoline agonists are cabergoline and bromocriptine and examples of non-ergoline agonists are pramipexole, ropinirole and rotigotine. Ergoline agonists have been linked to cartilage formation in heart valves.[1][2]

Dopamine agonists are primarily used in the treatment of the motor symptoms of Parkinson's disease, and to a lesser extent, in hyperprolactinemia and restless legs syndrome.[3][4] They are also used off-label in the treatment of clinical depression. One notable risk in the use of dopamine agonist is an increased risk of developing impulse control disorders.[4]

## Contents

* 1 Medical uses
* 1.1 Parkinson's disease
* 1.1.1 Treatment of depression in Parkinson's patients
* 1.2 Hyperprolactinemia
* 1.3 Restless leg syndrome
* 2 Adverse effects
* 2.1 Side effects
* 2.2 Interactions
* 3 Ergoline agonists
* 4 Pharmacokinetics
* 4.1 Ergolines
* 4.1.1 Bromocriptine
* 4.1.2 Pergolide
* 4.2 Non-ergolines
* 4.2.1 Pramipexole
* 4.2.2 Ropinirole
* 4.2.3 Rotigotine
* 5 Mechanism of action
* 5.1 Bromocriptine
* 5.2 Pramipexole
* 6 Structure–activity relationship
* 6.1 Crossing the blood brain barrier
* 6.2 Dopamine
* 6.3 Ergoline derivatives
* 6.3.1 Bromocriptine
* 6.4 Non-ergoline derivatives
* 6.4.1 Apomorphine
* 6.4.2 Rotigotine
* 7 Members
* 7.1 Partial agonist
* 7.2 Agonists of full/unknown efficacy
* 7.3 Related class of drugs: Indirect agonists
* 8 History
* 9 See also
* 10 References
* 11 Further reading
* 12 External links

## Medical uses

### Parkinson's disease

Dopamine agonists are mainly used in the treatment of Parkinson's disease.[3] In Parkinson's disease dopaminergic (neurons that produce the neurotransmitter dopamine) neurons in the brain slowly break down and can eventually die. With decreasing levels of dopamine, the brain cannot function properly. This causes abnormal brain activity, which ultimately leads to the symptoms of Parkinson's disease.[5] In their function as a treatment for Parkinson's disease, dopamine agonists act directly on the dopamine receptors and mimic dopamine's effect.[6]

dopamine

#### Treatment of depression in Parkinson's patients

Depressive symptoms and disorders are common in patients with Parkinson's disease and can affect their quality of life.[7] 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.[8] 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.[7][9]

### Hyperprolactinemia

Dopamine inhibits the production of prolactin in the human body. Therefore, anything that disrupts the production of dopamine would cause an increase in the production of prolactin. The ergoline-derived dopamine agonists bromocriptine and cabegoline are used in the treatment of hyperprolactinaemia.[10] These agents are associated with the reduction in the size of prolactinomas.[11] It is believed that they do so by suppressing the hypersecretion of prolactin, resulting in normal gonadal function.[11]

### Restless leg syndrome

Numerous clinical trials have been performed to assess the use of dopamine agonists for the treatment of restless legs syndrome (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.[12]

## Adverse effects

### Side effects

Between the two classes of dopamine agonists, ergolines tend to cause the most side effects due to their lack of specificity, targeting D1, 5-HT and adrenergic receptors in addition to their intended D2 receptor target.[6] In addition, the risk of side effects is much higher in the elderly than the general population.

The most common adverse effects are constipation, nausea and headaches. Other serious side effects are hallucinations, peripheral edema, gastrointestinal ulcers, pulmonary fibrosis and psychosis.[6][13]

Dopamine agonists have been linked to cardiac problems, with side effects such as hypotension, myocardial infarction, congestive heart failure, cardiac fibrosis, pericardial effusion and tachycardia.[6] A high risk for valvular heart disease has been established in association with ergot-derived agonists especially in elderly patients with hypertension.[14]

In some studies, almost 30% of patients are reported to have suffered from somnolence and sleep attacks when using dopamine agonists. Daytime sleepiness, insomnia and other sleep disturbances are also frequently associated with the use of these drugs.[6][15][16]

Impulse control disorder, which manifests in behaviors such as gambling, hypersexuality, shopping addiction[17] or binge eating, can be another serious adverse effect of dopamine agonists.[4][18]

After long-term use of dopamine agonists a withdrawal syndrome may occur when discontinuing the drug or reducing the dose. The following side effects are possible: anxiety, panic attacks, dysphoria, depression, agitation, irritability, suicidal ideation, fatigue, orthostatic hypotension, nausea, vomiting, diaphoresis, generalised pain and drug cravings. For some individuals, these withdrawal symptoms are short-lived, and they make a full recovery. For others, a protracted withdrawal syndrome may occur with symptoms persisting for months or years.[19]

### Interactions

Dopamine agonists interact with a number of drugs but there is little evidence that they interact with other Parkinson's drugs. In most cases there is no reason not to co-administer Parkinson's drugs, but there have been indications that the concurrent use of dopamine agonists with L-DOPA can cause psychosis, and therefore in these cases it is recommended that either the dopamine agonist(s) be discontinued or the dose of L-DOPA reduced. Since ergot-dopamine agonist have antihypertensive qualities it is wise to monitor blood pressure when using dopamine agonists with antihypertensive drugs to ensure that the patient does not get hypotension. That includes the drug sildenafil which is commonly used to treat erectile dysfunction but also used for pulmonary hypertension.[20]

There is evidence that suggests that since ergot dopamine agonists are metabolized by CYP3A4 enzyme concentration rises with the use of CYP3A4 inhibitors. For example, in one study bromocriptine was given with a CYP3A4 inhibitor and the AUC (area under the curve) increased 268%. Ropinirole is a non-ergot derived dopamine agonist and concomitant use with a CYP1A2 inhibitor can result in a higher concentration of ropinirole. When discontinuing the CYP1A2 inhibitor, if using both drugs, there is a chance 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.[13]

## Ergoline agonists

Ergoline, which forms the core structure of the subclass of dopamine agonists that share its name

Ergoline agonists share the same base ergoline structure, which is derived from the ergot fungus.[21] Ergot alkaloids are divided into two groups: amino acid ergot alkaloids and amine ergot alkaloids.[22]

In terms of efficacy, there does not seem to be much difference between ergoline agonists and their non-ergoline counterparts. However, ergolines are known to have a more concerning side effect profile, chiefly the added risk of valvular heart disease and cartilage formation within the heart valves.[1][2][23] In addition, ergoline agonists are less specific than non-ergoline agonists, targeting both 5-HT receptors and adrenergic receptors in addition to the primary D2 receptor targets.[6] It is for this reason that non-ergoline agonists are currently more preferred for treatment.

## Pharmacokinetics

### Ergolines

#### Bromocriptine

Absorption of bromocriptine oral dose is approximately 28%; however, only 6% reaches the systemic circulation unchanged, due to a substantial first-pass effect. Bromocriptine reaches mean peak plasma levels after about 1–1.5 hours after a single oral dose. The drug has high protein binding, ranging from 90-96% bound to serum albumin. Bromocriptine is metabolized by CYP3A4 and excreted primarily in the feces via biliary secretion. Metabolites and parent drugs are mostly excreted via the liver, but also 6% via the kidney. It has a half-life of 2–8 hours.[6]

#### Pergolide

Pergolide 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. The major route of excretion is through the kidneys.[6][24]

Drug  | Maintenance  | Half-life  | Protein binding  | Peak plasma  | Metabolism  | Excretion

|
|
|
|
|
|

Bromocriptine  |

Oral, 2.5–40 mg/day

| 2–8 hours  | 90-96%  | 1-1,5 hours  |

Hepatic, via CYP3A4, 93% first-pass metabolism

| Bile, 94-98%

Renal, 2-6%

Pergolide  |

Oral, 0.05 mg/day Usual response up to 0.1 mg per day

| 27 hours  | 90%  | 2–3 hours  | Extensively hepatic  | Renal, 50%

Fecal 50%

### Non-ergolines

#### Pramipexole

Pramipexole, in its instant release formulation, reaches maximum plasma concentration 1–3 hours post-dose. It is about 15% bound to plasma proteins and the metabolism is minimal. The elimination half-life of pramipexole is varies with age, being approximately 8 hours in younger subjects and 12 hours in the elderly.[6][25] The drug is mostly excreted in the urine, around 90%, but also in feces.[6]

#### Ropinirole

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 studies show that the enzyme involved in the metabolism of ropinirole is CYP1A2.[26]

#### Rotigotine

Since rotigotine is a transdermal patch it provides continuous drug delivery over 24 hours.[27] It has a half-life of 3 hours and the protein binding is around 92% in vitro and 89.5% in vivo. 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%).[6]

Drug  | Maintenance  | Half-life  | Protein binding  | Peak plasma  | Metabolism  | Excretion

|
|
|
|
|
|

Pramipexole  |

Oral, 0.125 mg 3x/day (IR) Oral, 0.375 mg/day (ER)

| 8–12 hours  | 15%  | 1–3 hours  | Minimal < 10%  | Urine 90%

Fecal 2%

Ropinirole  |

Oral, 0.25 mg 3x/day (IR) Oral, 2 mg/day (ER)

| 5–6 hours  | 10-40%  | 1–2 hours  | Hepatic, via P450 CYP1A2 — can increase ↑ INR  | Renal > 88%
Rotigotine  |

Transdermal, 2 – 4 mg/day

| 3 hours  |

92%

| 24 hours  | Hepatic (CYP-mediated).  | Urine 71%

Fecal 23%

## Mechanism of action

The dopamine receptors are members of the G protein-coupled receptors superfamily with seven transmembrane domains.

G protein-coupled receptors

Due to their mechanism of action on adenylate cyclase enzyme, dopamine receptors are subdivided into two subclasses: D1-like and D2-like. D1\- and D5-receptors belong to the D1-like family and the D2-like family includes D2, D3 and D4 receptors.[6] D1-like receptors are primarily coupled to Gαs/olf proteins and activates adenylate cyclase which increases intracellular levels of cAMP, they also activate the Gβγ complex and the N-type Ca2+ channel. D2-like receptors decrease intracellular levels of the second messenger cAMP by inhibiting adenylate cyclase.[28][29]

### Bromocriptine

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.

### Pramipexole

Pramipexole 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.[30]

## 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 to activate receptors and their affinity to bind to receptors.[31]

### Crossing the blood brain barrier

Many molecules are unable to cross the blood–brain barrier (BBB). Molecules must be small, non-polar and lipophilic to cross over. Compounds without these qualities must have a specific transporter that can transport them over the BBB.[32] Dopamine cannot diffuse across the BBB because of the catechol group, it is too polar and therefore unable to enter the brain. The catechol group is a dihydroxy benzene ring.

The synthesis of dopamine consists of three stages. The synthesis process starts with an amino acid, called L-tyrosine. In the second stage L-DOPA (levodopa) 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.[33]

Levodopa is also too polar to cross the blood brain barrier but it is an amino acid and has a specialized transporter called L-type amino acid transporter or LAT-1 that helps it diffuse through the barrier.[34]

### 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 bonding between catechol hydroxyls and purine nitrogens and by electrostatic interactions between the protonated ammonium group of dopamine and a negative phosphate 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.[35]

### Ergoline derivatives

Central dopaminergic agonist properties of semisynthetic ergoline derivatives lergotrile, pergolide, bromocriptine, cabergoline and lisuride 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 groups (chemical formula: –CH2CH2CH3) frequently enhance dopamine agonist effects in the ergoline derivatives.

Bromocriptine

The (+)-enantiomer displays notably diminished activity whereas the (-)-enantiomer possess potent dopamine agonist properties.[35]

#### Bromocriptine

Bromocriptine has an amino acid ergot alkaloid structure.[22] It contains a bromine halogen 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.[36] It has shown to have equal affinity for D2\- and D3-receptor and much lower affinity for D1-receptor.[37]

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.[38]

Rotigotine

#### Apomorphine

Apomorphine has a catechol 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.[39] It is a chiral 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.[40]

#### Rotigotine

Rotigotine is a phenolic amine and thus has poor oral bioavailability and fast clearance from the body. Therefore, it has been formulated as a transdermal patch, first and foremost to prevent first pass metabolism in the liver.[41]

## Members

Examples of dopamine agonists include:

### Partial agonist

* Aripiprazole (Partial agonist of the D2 family receptors - Trade name "Abilify" in the United States; atypical antipsychotic)
* Brexpiprazole (Partial agonist of the D2 family receptors - Trade name "Rexulti" in the United States; atypical antipsychotic)
* Cariprazine (Partial agonist of the D2 family receptors and D3 receptor - Trade name "Vraylar" in the United States; atypical antipsychotic)
* Phencyclidine (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 (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 of 40-60%, binding affinity of Ki=5-10nM and EC50=50-90nM)[42]

### Agonists of full/unknown efficacy

* Apomorphine (Apokyn – used to treat Parkinson's disease & Restless leg syndrome ) – biased at the D1 receptor.[43]
* Bromocriptine (Parlodel – used to treat PD/RLS)
* Cabergoline (Dostinex – used to treat PD/RLS)
* Ciladopa (used to treat PD/RLS)
* Dihydrexidine (used to treat PD/RLS)
* Dinapsoline (used to treat PD/RLS)
* Doxanthrine (used to treat PD/RLS)
* Epicriptine (used to treat PD/RLS)
* Lisuride (used to treat PD/RLS)
* Pergolide (used to treat PD/RLS) – previously available as Permax, but removed from the market in the USA on March 29, 2007.[44]
* Piribedil (Pronoran and Trivastal – used to treat PD/RLS)
* Pramipexole (Mirapex and Sifrol – used to treat PD/RLS)
* Propylnorapomorphine (used to treat PD/RLS)
* Quinagolide (Norprolac – used to treat PD/RLS)
* Ropinirole (Requip[45] – used to treat PD/RLS)
* Rotigotine (Neupro – used to treat PD/RLS)
* Roxindole (used to treat PD/RLS)
* Sumanirole (used to treat PD/RLS)

Some, such as fenoldopam, are selective for dopamine receptor D1.[46]

### Related class of drugs: Indirect agonists

There are two classes of drugs that act as indirect agonists of dopamine receptors: dopamine reuptake inhibitors and dopamine releasing agents. These are not considered dopamine agonists, since they have no specific agonist activity at dopamine receptors, 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 and/or dextroamphetamine (used to treat ADHD, narcolepsy, and obesity)
* Bupropion (used to facilitate smoking cessation and treat nicotine addiction and clinical depression)
* Lisdexamfetamine (used to treat ADHD and binge eating disorder)
* Methylphenidate or dexmethylphenidate (used to treat ADHD and narcolepsy)
* Modafinil or armodafinil (used primarily to treat narcolepsy)

Other examples include:

* Cathinone
* Caffeine[47]
* Cocaine (anesthetic with no medical uses as a central nervous system stimulant)
* Methamphetamine (used in rare circumstances to treat ADHD and obesity)
* Phenethylamine (endogenous trace amine)
* p-Tyramine (endogenous trace amine)

## History

Since the late 1960 Levodopa (L-DOPA) has been used to treat Parkinson's disease but there has always been a debate whether the treatment is worth the side effects.[48] Around 1970 clinicians started using the dopamine agonist apomorphine alongside L-DOPA 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 bromocriptine was use widely after clinicians discovered its benefits in treating Parkinsons.[49] When using the two drug classes together there is a possibility to reduce the amount of L-DOPA by 20-30% and thus keeping the fluctuating motor responses to a minimum.[2] Dopamine agonists are often used in younger people as monotherapy and as initial therapy instead of L-DOPA.[2] 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.[6]

The early dopamine agonists, such as bromocriptine, were ergot derived and activated the D2-receptor.[2] 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.[6]

Due to the major adverse effects of ergot-derived dopamine agonists, they are generally not used in modern medicine and have mostly been abandoned in favor of non-ergot agonists such as pramipexole, ropinirole and rotigotine. They do not induce as serious side effects although common side effects are nausea, edema and hypotension. Patients have also shown impaired impulse control such as overspending, hypersexuality and gambling.[50]

## See also

* Dopamine antagonist
* Dopamine reuptake inhibitor
* Receptor agonist
* GABA receptor agonist
* Dopaminergic
* Serotonin agonist
* Adrenergic agonist (sympathomimetic)
* Parasympathomimetic drug (acetylcholine agonist)
* Histamine agonist

## References

1. ↑ 1.0 1.1 Antonini, Angelo; Poewe, Werner (2007). "Fibrotic heart-valve reactions to dopamine-agonist treatment in Parkinson's disease". The Lancet Neurology (Elsevier BV) 6 (9): 826–829. doi:10.1016/s1474-4422(07)70218-1. ISSN 1474-4422. PMID 17706566.
2. ↑ 2.0 2.1 2.2 2.3 2.4 "Dopamine agonists: their role in the treatment of Parkinson's disease". Journal of Neurology, Neurosurgery, and Psychiatry 68 (6): 685–9. June 2000. doi:10.1136/jnnp.68.6.685. PMID 10811688.
3. ↑ 3.0 3.1 "Increased neostriatal dopamine activity after intraperitoneal or intranasal administration of L-DOPA: on the role of benserazide pretreatment". Synapse 27 (4): 294–302. December 1997. doi:10.1002/(sici)1098-2396(199712)27:4<294::aid-syn3>3.3.co;2-z. PMID 9372552.
4. ↑ 4.0 4.1 4.2 "Trait Impulsivity as a Feature of Parkinson's Disease Treatment and Progression". Parkinsons Dis 2024. 2024. doi:10.1155/2024/8770997. PMID 38766569.
5. ↑ "Parkinson's Disease and Its Management: Part 1: Disease Entity, Risk Factors, Pathophysiology, Clinical Presentation, and Diagnosis". P & T 40 (8): 504–32. August 2015. PMID 26236139.
6. ↑ 6.00 6.01 6.02 6.03 6.04 6.05 6.06 6.07 6.08 6.09 6.10 6.11 6.12 6.13 "Side effects of a dopamine agonist therapy for Parkinson's disease: a mini-review of clinical pharmacology". The Yale Journal of Biology and Medicine 89 (1): 37–47. March 2016. PMID 27505015.
7. ↑ 7.0 7.1 "Treatment of depressive symptoms in Parkinson's disease". European Journal of Neurology 18 (Suppl 1): 11–5. March 2011. doi:10.1111/j.1468-1331.2010.03325.x. PMID 21255198.
8. ↑ "The role of dopamine agonists in the treatment of depression in patients with Parkinson's disease: a systematic review". Drugs 71 (3): 273–86. February 2011. doi:10.2165/11585380-000000000-00000. PMID 21319866.
9. ↑ Trenkwalder, Claudia (2005), "Parkinsonism", Principles and Practice of Sleep Medicine (Elsevier): pp. 801–810, doi:10.1016/b0-72-160797-7/50074-4, ISBN 978-0-7216-0797-9
10. ↑ Verhelst, Johan; Abs, Roger; Maiter, Dominique; van den Bruel, Annick; Vandeweghe, Mark; Velkeniers, Brigitte; Mockel, Jean; Lamberigts, Gerard et al. (1999-07-01). "Cabergoline in the Treatment of Hyperprolactinemia: A Study in 455 Patients" (in en). The Journal of Clinical Endocrinology & Metabolism 84 (7): 2518–2522. doi:10.1210/jcem.84.7.5810. ISSN 0021-972X. PMID 10404830.
11. ↑ 11.0 11.1 Webster, Jonathan; Piscitelli, Gabriella; Polli, Anna; Ferrari, Carlo I.; Ismail, Ikram; Scanlon, Maurice F. (1994-10-06). "A Comparison of Cabergoline and Bromocriptine in the Treatment of Hyperprolactinemic Amenorrhea". New England Journal of Medicine 331 (14): 904–909. doi:10.1056/NEJM199410063311403. ISSN 0028-4793. PMID 7915824.
12. ↑ "Randomized trials of dopamine agonists in restless legs syndrome: a systematic review, quality assessment, and meta-analysis". Clinical Therapeutics 32 (2): 221–37. February 2010. doi:10.1016/j.clinthera.2010.01.028. PMID 20206780.
13. ↑ 13.0 13.1 "A review of the receptor-binding and pharmacokinetic properties of dopamine agonists". Clinical Therapeutics 28 (8): 1065–1078. August 2006. doi:10.1016/j.clinthera.2006.08.004. PMID 16982285.
14. ↑ "Valvular heart disease in Parkinson's disease vs. controls: An echocardiographic study". Movement Disorders 21 (8): 1109–13. August 2006. doi:10.1002/mds.20887. PMID 16622856.
15. ↑ "Clinical review and treatment of select adverse effects of dopamine receptor agonists in Parkinson's disease". Drugs & Aging 27 (4): 295–310. April 2010. doi:10.2165/11318330-000000000-00000. PMID 20359261.
16. ↑ "Development of excessive daytime sleepiness in early Parkinson disease". Neurology 85 (2): 162–8. July 2015. doi:10.1212/WNL.0000000000001737. PMID 26085603.
17. ↑ "Author lost £500k to compulsive shopping - then found an explanation" (in en-GB). 2026-05-01. https://www.bbc.com/news/articles/cm2pzv484nlo.
18. ↑ "Reports of pathological gambling, hypersexuality, and compulsive shopping associated with dopamine receptor agonist drugs". JAMA Internal Medicine 174 (12): 1930–3. December 2014. doi:10.1001/jamainternmed.2014.5262. PMID 25329919.
19. ↑ "Dopamine agonist withdrawal syndrome: implications for patient care". Drugs & Aging 30 (8): 587–92. August 2013. doi:10.1007/s40266-013-0090-z. PMID 23686524.
20. ↑ "Drug interactions in the treatment of Parkinson's disease". Journal of Neurology 249 (Suppl 3): III/24–9. October 2002. doi:10.1007/s00415-002-1305-0. PMID 12522568.
21. ↑ Gerhards, Nina; Neubauer, Lisa; Tudzynski, Paul; Li, Shu-Ming (2014-12-10). "Biosynthetic Pathways of Ergot Alkaloids" (in en). Toxins 6 (12): 3281–3295. doi:10.3390/toxins6123281. ISSN 2072-6651. PMID 25513893.
22. ↑ 22.0 22.1 "Bromocriptine, a dopamine D(2) receptor agonist with the structure of the amino acid ergot alkaloids, induces neurite outgrowth in PC12 cells". European Journal of Pharmacology 598 (1–3): 27–31. November 2008. doi:10.1016/j.ejphar.2008.09.015. PMID 18835264.
23. ↑ Tran, Tanja; Brophy, James M.; Suissa, Samy; Renoux, Christel (2015-12-01). "Risks of Cardiac Valve Regurgitation and Heart Failure Associated with Ergot- and Non-Ergot-Derived Dopamine Agonist Use in Patients with Parkinson's Disease: A Systematic Review of Observational Studies" (in en). CNS Drugs 29 (12): 985–998. doi:10.1007/s40263-015-0293-4. ISSN 1179-1934. PMID 26585874. https://doi.org/10.1007/s40263-015-0293-4.
24. ↑ "The pharmacokinetics of pergolide in Parkinson's disease". Current Opinion in Neurology 16 (Suppl 1): S9-12. December 2003. doi:10.1097/00019052-200312001-00003. PMID 15180132.
25. ↑ Wilson, Sean M.; Wurst, Madeline G.; Whatley, Michael F.; Daniels, R. Nathan (2020-09-02). "Classics in Chemical Neuroscience: Pramipexole" (in en). ACS Chemical Neuroscience 11 (17): 2506–2512. doi:10.1021/acschemneuro.0c00332. ISSN 1948-7193. PMID 32786316. https://pubs.acs.org/doi/10.1021/acschemneuro.0c00332.
26. ↑ "Clinical pharmacokinetics of ropinirole". Clinical Pharmacokinetics 39 (4): 243–54. October 2000. doi:10.2165/00003088-200039040-00001. PMID 11069211.
27. ↑ "An update on pharmacological, pharmacokinetic properties and drug-drug interactions of rotigotine transdermal system in Parkinson's disease and restless legs syndrome". Drugs 75 (5): 487–501. April 2015. doi:10.1007/s40265-015-0377-y. PMID 25795100.
28. ↑ Peterson, Sean M.; Urs, Nikhil; Caron, Marc G. (2012-01-01), Robertson, David; Biaggioni, Italo; Burnstock, Geoffrey et al., eds., "Chapter 13 - Dopamine Receptors", Primer on the Autonomic Nervous System (Third Edition) (Academic Press): pp. 67–70, doi:10.1016/B978-0-12-386525-0.00013-5, ISBN 978-0-12-386525-0
29. ↑ "Dopamine D1-Like Receptor Family Signaling Pathways" (in en-us). https://www.rndsystems.com/pathways/dopamine-d1-receptor-family-signaling-pathways.
30. ↑ "3 partial agonist pramipexole on neuroleptic-induced extrapyramidal symptoms and symptoms of schizophrenia: a stage-1 open-label pilot study". Neuropsychiatric Disease and Treatment 15: 2195–2203. 2019. doi:10.2147/NDT.S205933. PMID 31496702.
31. ↑ "Ropinirole hydrochloride, a dopamine agonist". Acta Crystallographica Section C 62 (Pt 5): o265-7. May 2006. doi:10.1107/S0108270106010535. PMID 16679599. Bibcode: 2006AcCrC..62O.265R.
32. ↑ "Characteristics of compounds that cross the blood-brain barrier". BMC Neurology 9 (Suppl 1): S3. June 2009. doi:10.1186/1471-2377-9-S1-S3. PMID 19534732.
33. ↑ "Homeostatic mechanisms in dopamine synthesis and release: a mathematical model". Theoretical Biology & Medical Modelling 6 (1). September 2009. doi:10.1186/1742-4682-6-21. PMID 19740446.
34. ↑ "The 4F2hc/LAT1 complex transports L-DOPA across the blood-brain barrier". Brain Research 879 (1–2): 115–21. October 2000. doi:10.1016/s0006-8993(00)02758-x. PMID 11011012.
35. ↑ 35.0 35.1 "Structure-activity relationships of dopamine agonists". Annual Review of Pharmacology and Toxicology 23: 103–29. 1983. doi:10.1146/annurev.pa.23.040183.000535. PMID 6347047.
36. ↑ "Structure activity relationship and therapeutic uses of dopaminergic ergots". Neurochemistry International. Satellite Meeting of the XIth International Congress of Pharmacology 20 (Suppl): 211S–214S. March 1992. doi:10.1016/0197-0186(92)90241-I. PMID 1365428.
37. ↑ "Functional potencies of new antiparkinsonian drugs at recombinant human dopamine D1, D2 and D3 receptors". European Journal of Pharmacology 366 (2–3): 293–300. February 1999. doi:10.1016/S0014-2999(98)00896-6. PMID 10082211.
38. ↑ "Homology modeling of dopamine D2 and D3 receptors: molecular dynamics refinement and docking evaluation". PLOS ONE 7 (9). 2012-09-06. doi:10.1371/journal.pone.0044316. PMID 22970199. Bibcode: 2012PLoSO...744316P.
39. ↑ "Challenges and trends in apomorphine drug delivery systems for the treatment of Parkinson's disease". Asian Journal of Pharmaceutical Sciences. Formulation strategies and manufacturing technologies to enhance non-invasive drug delivery 13 (6): 507–517. 2018-11-01. doi:10.1016/j.ajps.2017.11.004. ISSN 1818-0876. PMID 32104425.
40. ↑ "Apomorphine in dopaminergic therapy". Molecular Pharmaceutics 3 (4): 380–5. 2006. doi:10.1021/mp060012c. PMID 16889431.
41. ↑ "Synthesis and SAR study of a novel series of dopamine receptor agonists". Bioorganic & Medicinal Chemistry 22 (1): 381–92. January 2014. doi:10.1016/j.bmc.2013.11.012. PMID 24296012.
42. ↑ "Dopamine D2High receptors stimulated by phencyclidines, lysergic acid diethylamide, salvinorin A, and modafinil". Synapse 63 (8): 698–704. 2009. doi:10.1002/syn.20647. PMID 19391150.
43. ↑ "Identification of G protein-biased agonists that fail to recruit β-arrestin or promote internalization of the D1 dopamine receptor". ACS Chemical Neuroscience 6 (4): 681–92. April 2015. doi:10.1021/acschemneuro.5b00020. PMID 25660762.
44. ↑ FDA Announces Voluntary Withdrawal of Pergolide Products
45. ↑ "A convenient synthesis of 4-(2-hydroxyethyl)indolin-2-one, a useful intermediate for the preparation of both dopamine receptor agonists and protein kinase inhibitors". Monatshefte für Chemie 145 (7): 1139–1144. April 17, 2014. doi:10.1007/s00706-014-1211-z.
46. ↑ "In vivo venodilator action of fenoldopam, a dopamine D(1)-receptor agonist". British Journal of Pharmacology 129 (5): 853–8. March 2000. doi:10.1038/sj.bjp.0703119. PMID 10696081.
47. ↑ Watanabe, H.; Uramoto, H. (June 1986). "Caffeine mimics dopamine receptor agonists without stimulation of dopamine receptors" (in en). Neuropharmacology 25 (6): 577–581. doi:10.1016/0028-3908(86)90208-X. PMID 3748312. https://linkinghub.elsevier.com/retrieve/pii/002839088690208X.
48. ↑ "Revisiting the Medical Management of Parkinson's Disease: Levodopa versus Dopamine Agonist". Current Neuropharmacology 14 (4): 356–63. 2016-04-08. doi:10.2174/1570159X14666151208114634. PMID 26644151.
49. ↑ "History of levodopa and dopamine agonists in Parkinson's disease treatment". Neurology 50 (6 Suppl 6): S2–10; discussion S44–8. June 1998. doi:10.1212/wnl.50.6_suppl_6.s2. PMID 9633679.
50. ↑ Golan, David E.; Armstrong, Ehrin J; Armstrong, April W (2017). Principles of pharmacology - the pathophysiologic basis of drug therapy. Philadelphia: Wolters Kluwer. pp. 214–215. ISBN 978-1-4511-9100-4.

## Further reading

* "Pathological gambling in two patients on dopamine replacement therapy for Parkinson's disease". Neurological Sciences 25 (2): 98–101. June 2004. doi:10.1007/s10072-004-0238-z. PMID 15221629.

## External links

* Dopamine+Agonists at the US National Library of Medicine Medical Subject Headings (MeSH)

* v
* t
* e

Dopamine receptor modulators

D1-like|

| Agonists|

* Benzazepines: 6-Br-APB
* Fenoldopam
* SKF-38,393
* SKF-77,434
* SKF-81,297
* SKF-82,958
* SKF-83,959
* Trepipam
* Zelandopam

* Ergolines: Cabergoline
* CY-208,243
* Dihydroergocryptine
* LEK-8829
* Lisuride
* Pergolide
* Terguride

* Dihydrexidine derivatives: A-77636
* A-86929
* Adrogolide (ABT-431, DAS-431)
* Dihydrexidine
* Dinapsoline
* Dinoxyline
* Doxanthrine

* Phenethylamines: BCO-001
* Deoxyepinephrine (N-methyldopamine, epinine)
* Dopexamine
* Etilevodopa
* Ibopamine
* L-DOPA (levodopa)
* Melevodopa
* L-Phenylalanine
* L-Tyrosine
* XP21279

* Others: A-68930
* Apomorphine
* Isocorypalmine
* Nuciferine
* PF-6649751
* PF 6669571
* Propylnorapomorphine
* Rotigotine
* SKF-89,145
* SKF-89,626
* Stepholidine
* Tetrahydropalmatine

|

Antagonists|

* Typical antipsychotics: Butaclamol
* Chlorpromazine
* Chlorprothixene
* Flupentixol (flupenthixol) (+melitracen)
* Fluphenazine
* Loxapine
* Perphenazine (+amitriptyline)
* Pifluthixol
* Thioridazine
* Thiothixene
* Trifluoperazine (+tranylcypromine)
* Zuclopenthixol

* Atypical antipsychotics: Asenapine
* Clorotepine
* Clotiapine
* Clozapine
* DHA-clozapine
* Fluperlapine
* Iloperidone
* Norclozapine
* Norquetiapine
* Olanzapine (++fluoxetine)
* Paliperidone
* Quetiapine
* Risperidone
* Tefludazine
* Zicronapine
* Ziprasidone
* Zotepine

* Others: Berupipam
* Ecopipam
* EEDQ
* Metitepine (methiothepin)
* Odapipam
* Perlapine
* SCH-23390

D2-like|

| Agonists|

* Adamantanes: Amantadine
* Memantine
* Rimantadine

* Aminotetralins: 5-OH-DPAT
* 7-OH-DPAT
* 8-OH-PBZI
* Rotigotine
* UH-232

* Ergolines: Bromocriptine
* Cabergoline
* Dihydroergocryptine
* Epicriptine
* Ergocornine
* Lergotrile
* Lisuride
* LSD
* Pergolide
* Terguride

* Dihydrexidine derivatives: 2-OH-NPA
* Ciladopa
* Dihydrexidine
* Dinoxyline
* N,N-Propyldihydrexidine

* Phenethylamines: Deoxyepinephrine (N-methyldopamine, epinine)
* Dopexamine
* Etilevodopa
* Ibopamine
* L-DOPA (levodopa)
* L-Phenylalanine
* L-Tyrosine
* Melevodopa
* XP21279

* Atypical antipsychotics: Alentemol (U-66444B)
* Aripiprazole (+sertraline)
* Aripiprazole lauroxil
* Bifeprunox
* Brexpiprazole
* Brilaroxazine
* Cariprazine
* F-15063
* Lumateperone
* Norclozapine

* Others: 3-PPP
* A-412997
* ABT-670
* ABT-724
* Adrafinil
* Aplindore
* Apomorphine
* Arketamine
* Armodafinil
* BP-897
* Captodiame
* CP-226,269
* Dizocilpine
* Esketamine
* Flibanserin
* GSK-789,472
* Ketamine
* Mesulergine
* Modafinil
* OSU-6162
* Pardoprunox
* PD-128,907
* PD-168,077
* PF-219,061
* PF-592,379
* Phencyclidine
* Piribedil
* Pramipexole
* Preclamol
* Propylnorapomorphine
* Pukateine
* Quinagolide
* Quinelorane
* Quinpirole
* RDS-127
* Ro10-5824
* Ropinirole
* Roxindole
* Salvinorin A
* SKF-83,959
* Sumanirole
* Talipexole
* Umespirone
* WAY-100,635

|

Antagonists|

* Typical antipsychotics: Acepromazine
* Acetophenazine
* Azaperone
* Benperidol
* Bromperidol
* Butaclamol
* Butaperazine
* Chloracizine
* Chlorproethazine
* Chlorpromazine
* Chlorprothixene
* Ciclindole
* Clopenthixol
* Clothixamide
* Clopimozide
* Droperidol
* Fluacizine
* Fluanisone
* Flucindole
* Fluotracen
* Flupentixol (flupenthixol) (+melitracen)
* Fluphenazine
* Fluprothixene
* Fluspirilene
* Haloperidol
* Homopipramol
* Lenperone
* Levomepromazine (methotrimeprazine)
* Levosulpiride
* Loxapine
* Mesoridazine
* Moperone
* Naranol
* Nemonapride
* Penfluridol
* Perathiepin
* Perazine
* Pericyazine (periciazine)
* Perphenazine (+amitriptyline)
* Piflutixol (pifluthixol)
* Pimozide
* Pipamperone
* Preclamol
* Prochlorperazine
* Promazine
* Prothipendyl
* Spiperone (spiroperidol)
* Sulforidazine
* Sulpiride
* Sultopride
* Teflutixol
* Thiopropazate
* Thioproperazine
* Thioridazine
* Thiothixene
* Timiperone
* Trifluoperazine (+tranylcypromine)
* Triflupromazine
* Trifluperidol
* Zetidoline
* Zuclopenthixol

* Atypical antipsychotics: Amisulpride
* Asenapine
* BL-1020
* Blonanserin
* Carpipramine
* Cinuperone
* Clocapramine
* Clorotepine
* Clotiapine (clothiapine)
* Clozapine
* Cyamemazine
* DHA-clozapine
* Dixyrazine
* Elopiprazole
* Flumezapine
* Fluperlapine
* Gevotroline
* Iloperidone
* Lurasidone
* Mazapertine
* Melperone
* Molindone
* Mosapramine
* Ocaperidone
* Olanzapine (+fluoxetine)
* Paliperidone
* Perospirone
* Piperacetazine
* Pipotiazine
* Piquindone
* Quetiapine
* Remoxipride
* Risperidone
* Sertindole
* Tefludazine
* Tenilapine
* Tiospirone
* Veralipride
* Zicronapine
* Ziprasidone
* Zotepine

* Antiemetics/gastroprokinetics/sedatives: Aceprometazine
* AS-8112
* Alimemazine
* Alizapride
* Benzquinamide
* Bromopride
* Clebopride
* Domperidone
* Eticlopride
* Hydroxyzine
* Itopride
* Metoclopramide
* Metopimazine
* Promethazine
* Thiethylperazine
* Trimethobenzamide

* Antidepressants: Amoxapine
* Nefazodone
* Opipramol
* Propiomazine
* Trimipramine

* Others: 3-PPP
* Alpiropride
* Azapride
* Buspirone
* Desmethoxyfallypride
* EEDQ
* F-15063
* Fallypride
* Fananserin
* Fenfluramine
* GSK-789,472
* Iodobenzamide
* Isocorypalmine
* L-741,626
* L-745,870
* Levofenfluramine
* LEK-8829
* Metergoline
* Metitepine (methiothepin)
* N-Methylspiperone
* Nafadotride
* Nuciferine
* PNU-99,194
* Pridopidine
* Raclopride
* Sarizotan
* SB-277,011-A
* Seridopidine
* Sonepiprazole
* Spiroxatrine
* Stepholidine
* SV-293
* Tetrahydropalmatine
* Tiapride
* UH-232
* Yohimbine

* See also: Receptor/signaling modulators
* Adrenergics
* Serotonergics
* Monoamine reuptake inhibitors
* Monoamine releasing agents
* Monoamine metabolism modulators
* Monoamine neurotoxins

* v
* t
* e

Pharmacomodulation

Types|

* ♦ Enzyme: Inducer
* Inhibitor

* ♦ Ion channel: Opener
* Blocker

* ♦ Receptor: Agonist
* Partial agonist
* Antagonist
* Inverse agonist
* Positive allosteric modulator (PAM)
* Negative allosteric modulator (NAM)

* ♦ Transporter [Reuptake vs Efflux]: Enhancer (RE)
* Inhibitor (RI)
* Releaser (RA)

* ♦ Miscellaneous: Precursor
* Cofactor

Classes|

| Enzyme|

see Enzyme inhibition

|

Ion channel|

See Ion channel modulators

Receptor &
transporter|

| BA/M|

| Adrenergic|

* Adrenergic receptor agonist (α
* β (1
* 2))
* Adrenergic receptor antagonist (α (1
* 2)
* β)
* Norepinephrine reuptake inhibitor (NRI)

|

Dopaminergic|

* Dopamine receptor agonist
* Dopamine receptor antagonist
* Dopamine reuptake inhibitor (DRI)

Histaminergic|

* Histamine receptor agonist
* Histamine receptor antagonist (H1
* H2
* H3)

Serotonergic|

* Serotonin receptor agonist
* Serotonin receptor antagonist (5-HT3)
* Serotonin reuptake inhibitor (SRI)

AA|

| GABAergic|

* GABA receptor agonist
* GABA receptor antagonist
* GABA reuptake inhibitor (GRI)

|

Glutamatergic|

* Glutamate receptor agonist (AMPA)
* Glutamate receptor antagonist (NMDA)
* Glutamate reuptake inhibitor

Cholinergic|

* Acetylcholine receptor agonist (Muscarinic
* Nicotinic)
* Acetylcholine receptor antagonist (Muscarinic
* Nicotinic (Ganglionic
* Muscular))

Cannabinoidergic|

* Cannabinoid receptor agonist
* Cannabinoid receptor antagonist
* Endocannabinoid enhancer (eCBE)
* Endocannabinoid reuptake inhibitor (eCBRI)

Opioidergic|

* Opioid modulator
* Opioid receptor agonist
* Opioid receptor antagonist
* Enkephalinase inhibitor

Other|

* Adenosine reuptake inhibitor (AdoRI)
* Angiotensin II receptor antagonist
* Endothelin receptor antagonist
* NK1 receptor antagonist
* Vasopressin receptor antagonist

Miscellaneous|

* Cofactor (see Enzyme cofactors)
* Precursor (see Amino acids)

* v
* t
* e

Euphoriants

* μ-Opioid receptor agonists (opioids) (e.g., morphine]], heroin, hydrocodone, oxycodone, opium, kratom)
* α2δ subunit-containing voltage-dependent calcium channels blockers (gabapentinoids) (e.g., gabapentin, pregabalin, phenibut)
* AMPA receptor antagonists (e.g., perampanel)
* CB1 receptor agonists (cannabinoids) (e.g., THC]], cannabis)
* Dopamine receptor agonists (e.g., levodopa)
* Dopamine releasing agents (e.g., amphetamine, methamphetamine]], MDMA, Chemistry:Mephedrone

See also: Recreational drug use

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