Paliperidone powder(invega) is a chemical substance, gray white to light orange solid. It is an active metabolite of risperidone, an atypical antipsychotic drug. It is a scientific research reagent and is widely used in molecular biology, pharmacology and other scientific research. Papperidone is a derivative of benzoisoxazole, an active metabolite of risperidone, 9-hydroxyrisperidone. It is a new antipsychotic drug, and its mechanism of action is not completely clear, which may be related to the blocking effect of dopamine D2 and 5-hydroxytryptamine 2A (5HT2A), which has an inhibitory effect on adrenalin α 1, α 2 and histamine H1 receptor have blocking effect on choline and adrenaline β 1 and β 2 receptor has no affinity, and its left-handed and right-handed bodies have similar pharmacological effects in vitro. In addition, it can increase prolactin levels.
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Chemical Formula |
C23H27FN4O3 |
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Exact Mass |
426 |
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Molecular Weight |
426 |
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m/z |
426 (100.0%), 427 (24.9%), 428 (2.7%), 427 (1.5%) |
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Elemental Analysis |
C, 64.77; H, 6.38; F, 4.45; N, 13.14; O, 11.25 |
Paliperidone Powder , with the chemical name of 3-[2-[4-(6-fluoro-1,2-benzoisoxazole-3-yl)-1-piperidinyl]-ethyl]-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4h-pyrido [1,2-a] pyrimidine-4-one, was developed by Johnson & Johnson company of the United States and was approved by FDA of the United States in December 2006.
Studies have shown that 1 can effectively delay the recurrence rate of schizophrenia, be used for acute short-term and long-term maintenance treatment of schizophrenia, reduce symptoms, and long-term use can effectively stabilize the patient's condition.
The synthesis methods of papperidone mainly include the following:
Condensation of 9-benzyloxy-3 - (2-chloroethyl) - 2-methyl-4h-pyrido [1,2-a] pyrimidine-4-one (5) and 2,4-difluorophenyl-4-piperidinyl ketone oxime, and closed loop synthesis of 1 after pyridine ring reduction, with an overall yield of 26.4%. The deficiency is that 2,4-difluorophenyl-4-piperidinyl ketone oxime has z/e-isomers, and subsequent purification is difficult; In addition, the reduction of pyridine ring is also easy to form oxime bond reduction, which affects the yield.
5 and 6-fluoro-3 - (4-piperidinyl) - 1,2-benzoisoenzole (7) are condensed, and then hydrogenated and reduced to 1 month, with an overall yield of 33% (calculated as 5). The deficiency of this method is that isoenzole ring is also easy to be hydrogenated.
3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4h-pyridine [1,2-a] pyrimidine-4-one is introduced into 9-position formyl group by Vilsmeier Haack reaction in the presence of DMF and phosphorus oxychloride, which is treated with hydrogen peroxide 1 formic acid or m-chloroperoxybenzoic acid (mcpba) to obtain 6, and then condensed with 7 hydrochloride to obtain 1. The yield of 6 prepared by this method is only 33.4%, and it is difficult to purify.
Using 2-amino-3-hydroxypyridine (2) as raw material, 6, 6 and 7 hydrochloride were obtained by benzyl protection, cyclization, chlorination and hydrogenation reduction deprotection, and 1 was obtained by condensation of 6 and 7 hydrochloride, with an overall yield of 26.1%.
The method of our laboratory has improved route 4: x2. After benzyl protection, 2-amino-3-benzyloxypyridine (3) is obtained. The reaction solvent is toluene instead of dichloromethane 6, and the yield is 80.6%; After treatment, it can be concentrated directly and then crystallized, and the operation is simple. 3. After cyclization and chlorination, 5 was obtained. During post-treatment, dilute with toluene and separate the solution while hot, with a yield of 85%; In this study, it was first neutralized with ammonia in ice water bath, and then extracted with dichloromethane. The yield could be increased to 92%. 5 was reduced and debenzylated to 6, and then replaced with 7 hydrochloride by nucleophilic substitution to 1. Acetonitrile water (4:1) was used instead of dmf'si as solvent, and the yield was 64.4%. The improved process conditions are mild and easy to operate. The total yield is 34.6%.
Paliperidone, as an atypical antipsychotic drug, occupies an important position in the field of psychiatric treatment. Its core use revolves around schizophrenia and schizophrenia, providing patients with dual protection of acute symptom control and long-term maintenance treatment through a multi-target neurotransmitter regulation mechanism.
Core clinical indications
1. Whole course management of schizophrenia
It is a first-line medication for the treatment of acute and maintenance phases of schizophrenia. In the acute phase, patients' pain is relieved by rapidly controlling positive symptoms (such as hallucinations, delusions, and mental disorders), while in the maintenance phase, the risk of disease deterioration is reduced by continuously suppressing symptom recurrence. Research has shown that its long-acting injectable formulations, such as paliperidone palmitate, injected every 28 days after the initial titration period, can significantly delay the recurrence time, especially for patients with poor compliance.
2. Treatment for Schizophrenia Disorder
For patients with schizophrenia and emotional symptoms (such as depression and mania) who have both symptoms, paliperidone achieves bidirectional regulation of symptoms by balancing the dopamine and serotonin systems. Its oral sustained-release formulations (such as Invega) ®) Administering once a day can maintain stable blood drug concentration and reduce emotional fluctuations.
3. Improvement of social functions
Outstanding performance in improving patients' social functioning. A study of 1429 patients with schizophrenia found that 98% of patients showed a significant improvement in their Social Function Score (SOFAS) after using Papanitazone Extended Release Tablets, manifested as enhanced social skills, occupational function recovery, and improved self-care abilities.
Multi target mechanism of action
1. Dual antagonism of neurotransmitters
By blocking dopamine D2 receptors and 5-hydroxytryptamine 2A (5-HT2A) receptors, "sensory motor blockade separation" is achieved. It has a high affinity for D2 receptors and can effectively reduce positive symptoms caused by dopamine overstimulation; Simultaneously, the antagonistic effect on 5-HT2A receptors can alleviate negative symptoms such as emotional apathy and social withdrawal, and reduce the risk of extrapyramidal reactions (EPS).
2. Other receptor regulatory effects
It has a mild blocking effect on adrenaline alpha 1, alpha 2 receptors and histamine H1 receptors, which may explain its sedative side effects; But it has no affinity for cholinergic receptors and adrenaline β 1 and β 2 receptors, so it rarely causes anticholinergic reactions (such as dry mouth, constipation) or cardiovascular side effects (such as hypotension, tachycardia).
3. Neuroprotective potential
Recent studies have found that paliperidone can counteract dopamine mediated neuronal damage by increasing cell viability and reducing the expression of apoptotic proteins. This mechanism may be related to the observed improvement in cognitive function during long-term use, but further clinical validation is needed.
In vivo study:
Paliperidone Powder significantly increased the accumulation of Rh123 and DOX in cells in a concentration dependent manner. Paliperidone at low concentrations (10 and 50 μ M) It works well on a β (25-35) and MPP (+), and only protect SH-SY5Y from hydrogen peroxide damage. Paliperidone(100 μ M) Completely reduce the reduction of fine chemicalbook cells induced by different pressures, regardless of its dose. Paliperidone has higher oxidative stress scavenging effects than other APDS in many ways, such as producing large amounts of glutathione, low HNE, and protein carbonyl products. Paliperidone enhanced dopamine toxicity at the highest dose and was the only AP that significantly increased cell activity (8.1%) compared with cells treated with dopamine alone.
In vitro study:
Paliperidone restores extracellular glutamate in the basal layer of the prefrontal cortex in rats. In rats, paliperidone also prevented acute MK-801-induced increases in extracellular glutamate. The combined administration of paliperidone and estitachemicalbooklopram restored the inhibition of NE neuron discharge rate and the percentage of sudden neuronal discharge. Paliperidone reduces biting and aggressive behavior in a dose-dependent manner at effective doses. Paliperidone has led to a significant reduction in attacks.
1. Pharmacokinetic studies:
Due to its active metabolite, Paliperidone is also widely used in pharmacokinetic studies. These studies aim to understand the conversion and clearance rates of drugs in the body, in order to help determine dosage and frequency of administration. By studying the metabolic pathways and elimination methods of Paliperidone, we can better understand its pharmacokinetic characteristics in the human body.
2. Spectroscopic research:
As an organic compound, Paliperidone can also be used for spectroscopic research. Nuclear magnetic resonance (NMR) spectroscopy and infrared spectroscopy can be used to determine and characterize the molecular structure of Paliperidone, and to help identify other structural and functional related chemical groups.
3. Research on chemical synthesis methods:
In the field of drug research and development, chemists are usually committed to developing efficient synthesis methods to prepare target compounds. The research on the chemical synthesis methods of Paliperidone helps to enhance understanding of this drug synthesis process and provides support for improving synthesis efficiency and yield. By improving and optimizing the synthesis route, production costs can be reduced and the needs of the drug market can be met.
Paliperidone is an antipsychotic drug and an active metabolite of risperidone. The chemical name is (9RS)-3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidyl] ethyl]-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-4-one. It is an organic compound with a bicyclic spiral skeleton, containing elements such as oxygen, nitrogen, fluorine, and carbon. The molecular formula is C23H27FN4O3, with a molecular weight of 426.48 g/mol.
The molecular structure of Paliperidone mainly consists of the following parts:
Benzene ring structure:
In the upper left corner of the molecule, there is a benzene ring containing nitro oxide, which is one of the active sites of the drug.
01
Piperidine ring:
The piperidine ring connected to the benzene ring contains a nitrogen atom, which, together with the substituent structure on the benzene ring, forms the core structure of the drug.
02
Imidazole ring:
An imidazole ring structure located on the right side of a molecule, containing two nitrogen atoms.
03
Side chain structure:
Connected to the pyridine ring, containing a 1-hydroxy-2-methylethyl structure.
04
Paliperidone exerts its anti schizophrenia therapeutic effect by regulating the neurotransmitter activity of dopamine and serotonin. Specific parts of its molecular structure bind to neurotransmitter receptors, affecting neural signal transduction and reducing the onset of symptoms of schizophrenia.
FAQ
Is paliperidone the same as abilify?
The mechanism of action of paliperidone, as with other drugs having efficacy in schizophrenia, is unknown, but it has been proposed that the drug's therapeutic activity in schizophrenia is mediated through a combination of central dopamine Type 2 (D2) and serotonin Type 2 (5HT2A) receptor antagonism.
Is paliperidone a mood stabilizer?
Although the mechanism of regulation of these three drugs appears to involve different pathways, paliperidone induced changes in expression that resembled those observed with lithium and valproic acid at the synaptic level supporting its use as a mood stabilizer.
Is paliperidone a high risk medication?
IMPORTANT WARNING: has been expanded. Older adults with dementia (loss of memory and brain function) may have an increased risk of death if treated with antipsychotic medications such as paliperidone. Older adults with dementia may also have an increase risk of stroke or ministroke during treatment with antipsychotics.
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