What Are the Different Types of Dopamine Agonists?

Dopamine (DA) is a precursor substance for the synthesis of adrenaline and norepinephrine in the body. Dopamine receptor agonists are a class of drugs that are similar to dopamine in molecular conformation and can directly act on dopamine receptors ^[1] . With the further study of its pharmacological effects, dopamine receptor agonists will be widely used in clinical practice, and can find high-efficiency, low-side-effect drugs, thereby making greater contributions to human health.

Dopamine (DA) is a precursor substance for the synthesis of adrenaline and norepinephrine in the body. Dopamine receptor agonists are a class of drugs that are similar to dopamine in molecular conformation and can directly act on dopamine receptors ^[1] . With the further study of its pharmacological effects, dopamine receptor agonists will be widely used in clinical practice, and can find high-efficiency, low-side-effect drugs, thereby making greater contributions to human health.

1 Dopamine receptor agonists 1. Classification, distribution, and function of dopamine receptor agonists

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There are five types of dopamine receptor agonists, which can be grouped into two categories, d1 and d5 belong to one category (D1), and the other three belong to the other category (D2). The difference between the two categories is that when they are stimulated, the activity of adenylate cyclase changes. D1 promotes its activity, while D2 does not change or decrease its activity. Dopamine receptors are distributed throughout the body, of which D1 is distributed in the kidney, adrenal glands, heart, and mesenteric arteries. D2 mainly acts on sympathetic ganglia and adrenergic nerve endings. It can stimulate the heart, kidney, mesenteric artery, and sympathetic ganglia by stimulating adenylate cyclase to produce cAMP, promote sodium ion excretion, and promote renin secretion by mesangial cells. And finally releases the adrenal and norepinephrine.

2 Dopamine receptor agonist 2. Mechanism of action of dopamine receptor agonist

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Human movement is regulated by the striatum-thalamus-cortex circuit and is divided into direct and indirect pathways. Dopamine can increase D1 receptor neuron activity and decrease D2 receptor neuron activity. Dopamine can regulate two pathways. If dopamine is reduced, the hypothalamus nucleus and Gpi are abnormally activated. Therefore, dopamine receptor agonists can increase dopaminergic stimulation and regain equilibrium. Dopamine receptor agonists can also stimulate other receptors to exert peripheral effects.

3 Dopamine receptor agonist 3, clinical application of dopamine receptor agonist

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( 1 ) Status of dopamine receptor agonists in the treatment of Parkinson's disease and its advantages

Parkinson disease (PD) is a chronic progressive disease. Its main pathological feature is degeneration of dopaminergic neurons in the nigrostriatal striatum, leading to a decrease in dopaminergic nerve endings and striatum. The clinical symptoms are tremor. Paralysis, rigidity or dyskinesia. L-dopa preparation has been considered as the most effective drug for PD for more than 40 years. It has good curative effect on various PD symptoms, but long-term and / or large-scale application is prone to decrease in efficacy and "end-dose phenomenon." "," Switching phenomenon "and other complications. Dopamine receptor agonists can overcome L-dopa deficiency and enhance L-dopa's single effect to delay the occurrence of complications. The combined use of low-dose L-dopa and dopamine receptor agonists is equivalent to large-dose L-dopa alone, with a significantly reduced incidence of side effects. The combination of dopamine receptor agonist and compound dopa in the early stage can not only improve the curative effect and reduce the dosage of compound dopa, but also reduce or avoid the occurrence of symptom fluctuation or dyskinesia. The treatment of compound dopa in the late stage of the disease has already produced symptom fluctuation or exercise. People with disabilities can reduce or eliminate these symptoms by adding dopamine receptor agonists while reducing the amount of compound dopa. In the late stage of the disease, due to the nigrostriatal dopaminergic system, exogenous L-dopa cannot be decarboxylated into dopamine. At this time, compound dopamine is completely ineffective, and it is effective if dopamine receptor agonists are used. Dopamine receptor agonists have become the fastest-growing PD therapies.

Bromocriptine is mainly a D2 receptor agonist and has a slight antagonistic effect on the D1 receptor. In small doses, it activates the presynaptic membrane autoreceptor D2, which reduces the release of dopamine, so it can treat dance-like hyperactivity. The effect of PD alone is not good, and the combination with L-dopa preparation can reduce motion fluctuation and on-off phenomenon. The ergot gland has the function of exciting D1 and D2 receptors, and is mainly used for those who have obvious on-off phenomenon in compound dopamine therapy. Cabergoline is a new type of long-acting ergot base selective D2 receptor agonist. When used in combination with L-dopa preparations, it can reduce the amount of dopa, reduce the fluctuation of exercise symptoms and dystonia during the "off" period. Pergolide alone can achieve better results in the treatment of early PD, and most patients with intermediate and advanced PD advocate combination with L-dopa. Compared with bromocriptine and pergolide, alpha-dihydroergocryptine has better efficacy and fewer side effects. Alpha-dihydroergocryptine can activate D2 receptors, improve potential abnormalities due to the D1 / D2 receptor imbalance, and protect neurons from peroxidation

Praxox has sufficient natural activity at the D2 receptor and is highly selective. It has a stronger agonistic effect on dopamine receptors and a small effect on adrenal glands or 5-HTergic receptors. It not only has a good effect in the treatment of PD, but also because of its active effect on D3, it may control the psychological complications of PD. Beneficial, may be a potential antidepressant, used alone or in combination with classic antidepressants, it is more beneficial for patients with PD with depression. When used alone or in combination with L-dopa, it can reduce the dose of L-dopa And side effects, alleviate depressive symptoms in patients. Pirbedil is a non-ergot synthetic dopamine agonist, which has an agonistic effect on the D1 and D3 receptors. Clinical studies have proven that pirbedil can be used alone or in combination with compound dopa. Improve the non-motor symptoms such as mental, emotional and sleep in early PD patients, and significantly delay the decline of striatum DAT activity, and effectively reduce the fluctuation of end-dose symptoms and peak dose dyskinesia, which can achieve relatively stable DR stimulation. Can effectively treat PD for a long time, and reduce the purpose of dyskinesia and fluctuation of symptoms. Early combined application of pirbedil may significantly improve the quality of life of patients. Apomorphine is a broad-spectrum dopamine agonist for PD. It has a strong agonistic effect on D1, D2, and D3 receptors. Subcutaneous injection of apomorphine in combination with oral L-dopa preparations can enhance the efficacy of L-dopa and reduce Side effects caused by L-dopa.

( 2 ) Neuron protection of dopamine receptor agonists

The neuron protection of dopamine receptor agonists is one of the hot topics of recent research. From a biochemical perspective, neuroprotection refers to protecting neurons from various pathologies that lead to cell death related to the etiology of PD. The effects of biochemical factors control the symptoms of PD by preventing or delaying the process of PD. In the study of mouse models of cerebral ischemia MPTP and 6-hydroxydopa, several dopamine receptor agonists have shown neuronal protective effects. For example, in the study of gerbil cerebral ischemia, bromocriptine, Pergolide or risulide has neuroprotective effects on hippocampal CA1 neurons, and this effect is mainly related to maintaining the expression of peroxide dismutase in hippocampal neurons. The study of the D2 / D3 receptor agonist pramipexole has shown that it can specifically reduce the nigrostriatal dopaminergic neuron loss in mice, but the dose-related average dose is 1 mg / kg. The results of apomorphine, bromocriptine, pergolide, pramipexole, and ropinirole have all confirmed the antioxidant effects of dopamine receptor agonists. In vitro tests have found that 200 ~ 500 mol of pergolide and 30 mol of pramipexole can effectively scavenge free radicals. At the same time, 10 mol or lower of pramipexole has neuroprotective effects, which may be earlier than its oxidation. Bromocriptine scavenges free radicals, such as hydroxyl radicals and superoxide radicals, and can inhibit lipid peroxidation. It has a powerful antioxidant effect. Pretreatment of mice with bromocriptine completely protects them from 6-hydroxyl Neurotoxic effects of dopamine. In addition, the pretreatment of bromocriptine and ropinirole in the culture of midbrain neurons can resist the neurotoxicity caused by glutathione. If the dopamine receptor agonist is used together with neurotoxicity, its protective effect will disappear. And this protective effect can be antagonized by D2 receptor blockers. The D2 / D3 receptor agonist ropinirole has all the weak free radical scavenging effects in vitro, fights the toxic effects of 6-hydroxydopa in mice, and protects the nigrostriatal dopaminergic neurons, so the dopamine receptor is activated. Agents can reduce the production of hydrogen peroxide (H2O2) and toxic hydroxyl radicals (· OH), keep cells in a low oxidative stress state, and remove free radicals produced in the body by neurotoxins such as 6-hydroxydopa and MPTP, protecting Striatum dopaminergic neurons delay motor complications. Numerous animal experiments have shown that dopamine receptor agonists have neuroprotective effects and can delay the progression of PD.

( 3 ) Effect of dopamine receptor agonist blood pressure and heart rate

Recent studies have shown that the central dopamine system is not only related to physical movements but also participates in the regulation of cardiovascular movements. The application of small doses of dopamine can also stimulate surrounding specific dopamine receptors to cause visceral vasodilation. At high doses, 1 adrenergic receptors can be activated. The body exerts positive force and time-varying effects on the heart, and even activates 1 and 2 adrenergic receptors to cause vasoconstriction and increase blood pressure. Some experimental results show that the microinjection of dopamine or dopamine receptor agonist apomorphine into the tail nucleus can cause blood pressure and heart rate of normal blood pressure rats anesthetized by urethane. The D1-like receptor agonist Ibopamine (Isopramine) is used in small doses to dilate blood vessels through D2-like receptor-mediated inhibition of norepinephrine release and direct vasodilatory action mediated by D1-like receptors. Fenoldopam (Fenoldopam) is a selective D1-like receptor agonist. Its vasodilator effect is 6-9 times that of dopamine. It can expand renal coronary and mesenteric arteries, reduce postventricular load, and increase renal blood flow. Fenoldopam has achieved satisfactory results in the treatment of hypertension crisis. Pilmer et al. Reported 200 cases of intravenous application of Fenoldopam in patients with hypertension crisis and found that Fenoldopam is as effective as sodium nitroprusside and has no adverse reactions to sodium nitroprusside. The effect of Fenoldopam on the rabbit renal arteries, lungs, mesenteric arteries, and femoral arteries cAMP production system, can increase the cAMP production of pulmonary arteries, renal arteries, and mesenteric arteries in a concentration-dependent manner, dilate renal arteries, coronary arteries, and mesenteric arteries, thereby generating blood vessels Diastolic effect. D2-like receptor agonists. Although these drugs can lower blood pressure, they can pass through the blood-brain barrier and are often accompanied by severe side effects caused by central dopamine receptor agonism, so they are not used to treat cardiovascular disease.

( 4 ) Clinical application of dopamine receptor agonists in other diseases

Restless legs syndrome is a common neurological disease. Researchers have discovered that dysfunction of dopaminergic neural pathways may be a common underlying pathogenic mechanism of restless legs syndrome and PD, and dopamine receptor agonists such as bromocriptine, pergolide, and non-ergotergic newly synthesized agonists for PD Milapa, cabergoline, and ropinirole can effectively control and improve restless legs syndrome.

The high fever that dopamine receptor agonist bromocriptine has not been able to control in the etiology of the acute stage of the primary disease and that some artificial hibernation and cooling measures have not effectively controlled, can make it quickly relieve or even completely reduce fever. The mechanism of drug action is mainly related to the reduction of central dopaminergic DA2 receptor activity and the number of receptors, especially in the hypothalamic basal ganglia limbic system. Blockage of central dopamine receptors or depletion of dopamine lead to disturbances in central temperature regulation. Dopamine and other monoamine neurotransmitters are maintained in several neuromuscular balances. Uncontrolled hypothalamic body temperature causes disturbance of consciousness, while the DA2 receptor agonism of bromocriptine central can directly interact with the hypothalamic body temperature regulation center to achieve cooling. Amazing effect.

Prolactin adenoma is the most common pituitary adenoma. Prior to the 1980s, prolactin adenomas had been treated with surgery and radiation. The advent of dopamine receptor agonists has fundamentally changed the treatment of prolactin adenomas. Bromocriptine is a representative drug for dopamine receptor agonists in the treatment of prolactin adenomas, and it is the treatment of choice for most prolactin adenomas. The mechanism of action is that it binds to the D2 receptor on the membrane of normal cells or tumor cells, which leads to a decrease in the activity of adenylate cyclase in the cell, thereby reducing prolactin synthesis and release.

Acromegaly is a chronic disease that is mainly characterized by progressive facial changes and different degrees of neuro-articular damage, and can be secondary to cardiovascular system complications. Excessive growth hormone (GH) secretion by pituitary tumors is responsible for acromegaly The main cause of the disease. Dopamine receptor agonists can inhibit the release of GH by stimulating dopamine receptors under the thalamus. Commonly used dopamine receptor agonists include the ergot derivative bromocriptine, thioergoline mesylate and cabergoline, and non-ergot derivatives such as quinolid.

In the research and treatment of schizophrenia, dopamine receptor partial agonists have become a new class of antipsychotic drugs, which mainly act on the D2 receptor, serotonin 1A (5-HT1A) and 5-HT2A. Its representative drugs such as aripiprazole (Aripiprazole), its mechanism of action is different from classic and non-classical antipsychotic drugs, it has the dual partial agonism of D2 and 5-HT1A receptors, it has an antagonistic effect on 5-HT2A. DA receptor agonists can improve positive symptoms, negative symptoms, and cognitive deficits in schizophrenia, but rarely cause extrapyramidal reactions (EPS) caused by classic drugs, increased serum prolactin; and atypical drugs Adverse reactions such as increased mass and metabolic abnormalities are safe and well tolerated.

In the treatment of male erectile dysfunction (ED), the role of apomorphine, a dopamine receptor agonist in the central brain, is receiving increasing attention. Subcutaneous injection of apomorphine can induce erectile reactions, but its adverse effects of nausea and vomiting are very serious, which limits its clinical application. The sublingual route is the fastest absorption route of apomorphine. Sublingual apomorphine belongs to the central nervous system. Animal experiments of ED drugs have shown that after taking apomorphine under the tongue and acting on the dopamine D2 receptor, activating the oxytocin neurons in the paraventricular nucleus of the hypothalamus increases the release of oxytocin by the oxytocin neurons. Oxytocin is an important central transmitter that controls penile erections. Oxytocin passes the central signal through the parasympathetic nerves of the spinal cord to the erection center of the iliac pulp. The erection center of the iliac pulp sends a signal to the penile area, activates the NO-CGMP pathway, and eventually results in an erection of the penis.

4 Dopamine receptor agonists 4, common side effects of dopamine receptor agonists

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Almost all dopamine receptor agonists have symptoms of the upper gastrointestinal tract (loss of appetite, nausea, vomiting, etc.). Symptoms of the circulatory system and central nervous system are side effects caused by the promotion of dopamine neurotransmission. Drugs that stimulate vomiting of the medulla oblongata and dopaminergic neurotransmission in the stomach have more or less the above-mentioned side effects. The unique side effects of ergot derivatives dopamine are peripheral (lower limb, upper limb, face, etc.) edema, pulmonary pleura, posterior peritoneum, and fibrosis of heart valves. Recent studies have found that ergot alkaloid DA receptor agonists have adverse effects on the heart valve during clinical application, resulting in increased reflux. Patients with high doses of pergolide have a high risk of tricuspid regurgitation. By comparing valvular disease and patients without valvular disease, it is found that the cumulative dose and time of patients with valvular disease are related. Peripheral edema is common with ergot derivative dopamine, but it has also been reported to be found in non-ergot derivatives. In recent years, it has been found that dopamine, especially the non-ergot derivative dopamine, has the side effects of sudden sleep, so patients who drive by themselves should pay attention to it. Dopamine receptor agonists should gradually increase the dose from a small dose. If the adverse reaction is more serious, dopamine receptor antagonist-domperidone can be used.

5 Dopamine receptor agonist 5, dopamine receptor agonist withdrawal syndrome

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Dopamine agonist withdrawal syndrome (DAWS) refers to the dose-dependent reduction of dopamine agonist withdrawal syndrome, which can lead to clinically significant distress or social / occupational dysfunction. DAWS cannot be caused by clinical factors other than dopamine agonist reduction or discontinuation. Serious, rigid neuropsychiatric syndromes are difficult to treat with levodopa and other anti-Parkinson's drugs. The quality of life and social function of patients with DAWS are severely degraded, and suicidal behaviors may be present, which should be taken seriously by clinicians.

DAWS symptoms appear very slowly after dopamine receptor agonist reduction or discontinuation or gradually occur with dopamine receptor agonist reduction or the reduction begins. The clinical manifestations are highly rigid and resembling other psychostimulant withdrawal syndromes, as well as significant: mental symptoms: anxiety, panic attack, irritability, depression, excitement, irritability, fatigue, and drug craving; autonomic symptoms : Orthostatic hypotension, flushing, nausea, sweating, etc .; sleep disorders; paresthesia: non-motor symptoms such as general body pain. Most symptoms after DBS, such as: anxiety, panic, agoraphobia, irritability, fatigue, orthostatic hypotension, sweating, and pain are common, are non-specific symptoms and are not easily recognized, and delayed apathy and More chronic symptoms, such as significant depression, represent a type of prolonged withdrawal syndrome and / or a manifestation of dopamine deficiency in the midbrain cortex, which were previously controlled only by dopamine receptor agonists. Although the dose of dopaminergic agents can be reduced immediately after surgery, the appearance of indifference can be delayed by an average of nearly 6 months. In a small number of patients, depression can be triggered by major life events. However, in the vast majority of patients, depression can occur at the same time as indifference or after a brief appearance of isolated indifference.