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Dynorphin A is a 17 peptide dynorphin extracted from pig pituitary gland, which has extremely strong opioid like activity. It has many fragments such as dynorphinA (1-8) [dynorphinA (1-8)], dynorphinA (1-13) [dynorphinA (1-13)]], dynorphinA (1-17) [dynorphinA (1-17)], etc. Molecular formula C75H126N24O15, CAS 72957-38-1. It is generally a white or almost white powdery solid. It is a non optically active substance, that is, it has no optical rotation to light. It is a linear peptide composed of 13 amino acid residues, with specific spatial conformation and molecular structure. A class of morphine like active peptides with strong analgesic effects. Its precursor is prodynorphin. Dynorphins include dynorphinA and dynorphin B. Among them, dynorphinA is a 17 peptide, which is 700 times more active than leuprorelin and β- The activity of endorphins is 50 times stronger, and dynorphin B is 13 peptides. Dynorphins are widely distributed in the nervous system.
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As an important member of the endogenous opioid peptide family, dynorphin A (1-13) has gradually revealed its unique physiological functions and pharmacological potential since its first isolation from the pig pituitary gland in 1979. As a high affinity ligand for the kappa opioid receptor (κ - OR), it has shown broad application prospects in pain management, neuroprotection, emotion regulation, and cardiovascular regulation by regulating neurotransmitter release, neuronal excitability, and synaptic plasticity.
1. Analgesic mechanism at physiological concentration
By activating κ - OR at physiological concentrations, it inhibits the release of excitatory neurotransmitters such as glutamate from spinal dorsal horn neurons, reduces neuronal excitability, and thus alleviates pain. This effect has potential therapeutic value for acute pain (such as postoperative pain), chronic pain (such as arthritis) and neuropathic pain (such as diabetes peripheral neuropathy). For example, in animal models, intrathecal injection can significantly reduce formalin induced pain behavior, with effects comparable to morphine but lower addictive.
2. Dual role: Balancing analgesia and pain causing effects
Although the substance is a potent agonist of κ - OR, excessive or long-term activation may lead to pain sensitization through non opioid pathways such as NMDA receptors.
Research has shown that in neural injury models, elevated levels may exacerbate pain, while antagonizing kappa OR or NMDA receptors can reverse this effect. This discovery suggests that strict control of dosage and course of treatment is necessary in clinical applications to avoid the "pain relieving pain inducing" paradox.
3. Development of new analgesic drugs
Compared with traditional μ - opioid receptor agonists such as morphine, κ - OR agonists have advantages such as low addiction and low risk of respiratory depression. And its analogues (such as U50488H) have been regarded as important candidate molecules for the development of new analgesics. For example, U50488H demonstrated good safety in a myocardial ischemia-reperfusion injury model by activating κ - OR to reduce myocardial infarction area without causing respiratory depression.
1. The regulatory effect of cerebral ischemia-reperfusion injury
Myocardial ischemic preconditioning (IPC) can induce the release of this substance, enhancing the heart's tolerance to ischemia-reperfusion injury by activating κ - OR. Similar mechanisms also exist in cerebral ischemia: it can reduce brain edema, shrink the area of cerebral infarction, and improve memory impairment after ischemia. For example, a rat cerebral ischemia experiment showed that after injection into the lateral ventricle, the brain water content and lactate content were significantly reduced, and apoptosis of cortical and hippocampal cells was reduced.
2. Multi pathway protection mechanism
Its neuroprotective effect may be achieved through a combination of opioid receptor pathways (κ - OR) and non opioid receptor pathways (such as NMDA receptors).
Research has found that both kappa OR antagonists (nor BNI) and NMDA receptor antagonists (MK-801) can alleviate brain edema, suggesting that dynorphin A (1-13) may regulate neuronal survival through a dual pathway. In addition, stress induced behavioral disorders can be alleviated through the synergistic effect of the 5-HT system.
3. Clinical translational potential
The level of enkephalin A (1-13) in plasma significantly decreased within 72 hours of cerebral infarction and began to rise in the third week, consistent with cerebral edema, suggesting that it can serve as a biomarker for cerebral ischemia. In the future, exogenous supplementation of dynorphin (1-13) or regulation of its endogenous release may provide new strategies for stroke treatment.
1. The physiological basis of negative emotions
By activating κ - OR, the dopaminergic pathway in the midbrain limbic system (such as the amygdala and nucleus accumbens) is regulated, affecting reward mechanisms and emotional states. Animal experiments have shown that κ - OR agonists can induce depressive like behavior (such as prolonged immobility in tail suspension tests), while antagonists have antidepressant effects. For example, nor BNI can reverse the loss of pleasure caused by chronic stress, suggesting that the dynorphin (1-13)/κ - OR system may be an important therapeutic target for depressive disorders.
2. Bi directional regulation of drug addiction
Playing a complex role in drug addiction: on the one hand, activating κ - OR can reduce dopamine release and inhibit the reward effect of addictive drugs; On the other hand, long-term exposure to the substance may lead to tolerance and exacerbate addictive behavior.
For example, kappa OR antagonists can enhance the spontaneous activity of cocaine, while agonists reduce the self-administration behavior of morphine, providing a dual strategy for addiction treatment.
3. The regulatory role of stress response
Participate in the regulation of the hypothalamic pituitary adrenal axis (HPA axis), affecting the physiological and psychological responses of the body to stress. In the chronic stress model, elevated levels are associated with anxiety like behavior, and κ - OR antagonists can improve cognitive impairment caused by stress. This discovery provides new ideas for the treatment of anxiety disorders.
1. Protective mechanism of myocardial ischemic preconditioning
IPC activates κ - OR by releasing enkephalin A (1-13), reducing intracellular calcium overload and protease leakage in cardiomyocytes, thereby protecting the heart from ischemia-reperfusion injury. For example, U50488H can significantly reduce myocardial infarction area, while nor BNI blocks this effect, confirming the cardioprotective effect mediated by κ - OR.
2. Balance between vascular contraction and relaxation
Expressed in cerebral blood vessels, it can induce sustained vasoconstriction, but has a relaxing effect on soft membrane arteries and small arteries.
This dual regulation may be achieved through both the kappa OR and non kappa OR pathways. For example, during cerebral ischemia, its vasodilatory effect may improve brain tissue perfusion and alleviate ischemic injury.
3. Potential role of immune regulation
It can also regulate immune cell activity, affect heart rate, blood pressure, and inflammatory response. For example, activation of κ - OR can inhibit T cell proliferation, reduce the release of inflammatory factors, and thus play a protective role in autoimmune diseases. This discovery provides a new perspective on the interaction between cardiovascular disease and the immune system.
1. Analysis of opioid receptor function
As a highly selective tool drug for κ - OR, it is widely used in receptor localization, signal transduction, and drug screening research. For example, the structure of the dynorphin A (1-13) - κ - OR complex was analyzed using cryo electron microscopy technology, revealing its molecular mechanism of selective activation through complementary positive ECL2 region and negative receptor region, providing a structural basis for designing novel κ - OR ligands.
2. Research on the mechanism of neural signal transduction
It can be used to explore the molecular mechanisms of neuronal excitability regulation, synaptic transmission, and neural plasticity.
For example, in the pain model, dynorphin (1-13) affects the plasticity of spinal dorsal horn neurons by regulating glutamatergic synaptic transmission, thereby altering the pain perception threshold.
3. In depth exploration of disease mechanisms
In research on neurodegenerative diseases such as Alzheimer's disease, it can be used to reveal the association between the opioid peptide system and β - amyloid deposition, tau protein phosphorylation. For example, dynorphin (1-13) may slow down disease progression by regulating the activity of microglia and affecting neuroinflammatory responses.
Research has shown that myocardial ischemic preconditioning (IPC) can enhance the tolerance of the heart to subsequent sustained myocardial ischemia-reperfusion (I/R) injury. The protective effect of IPC on ischemic myocardium is mainly achieved by the release of endogenous substances triggered by ischemia. It is known that under normal conditions, the heart can synthesize Dyn and activate it κ The regulatory effect of opioid receptors on the cardiovascular system; During myocardial ischemia, endogenous Dyn may be released and increased through activation κ Opioid receptors are involved in the pathological process of myocardial ischemia. Therefore, this experiment aims to investigate whether endogenous Dyn plays an important role in the myocardial protective effect of IPC and its activation κ Does opioid receptors have a direct protective effect on ischemia-reperfusion myocardium.
(1) IPC may promote the release of endogenous opioid peptide Dyn in the body and increase plasma Dyn levels, which can be activated by κ Opioid receptors have a protective effect on the heart.
(2) Activation of exogenous opioid substance U50488H κ Opioid receptors can significantly reduce the size of myocardial infarction in I/R, reduce the leakage of proteases in myocardial cells, and have a direct protective effect on I/R myocardium.
(3) Give κ The specific antagonist of opioid receptors, Nor-BNI, can block the improvement of myocardial contraction function in I/R by IPC, further proving that κ Opioid receptors mediate the protective effect of IPC on I/R myocardium.
The chemical synthesis method of dynorphin (1-13) mainly includes the following steps:
Condensation reaction: C7H4O3+C4H6O2 → C10H8O5
Hydrolysis reaction: C10H8O5 → C7H4O3+C3H6O2
1. Raw material preparation
(1) Pre treatment of amino acids: Add the required 13 amino acids in sequence to the beaker and dissolve in an appropriate amount of water. Then filter it into a volumetric flask and wash the filter paper and beaker several times with distilled water to ensure the purity and sterility of the solution.
(2) Catalyst pretreatment: Select appropriate catalysts based on specific reaction conditions, such as concentrated sulfuric acid, phosphoric acid, or hydrogen chloride. Dissolve it in an appropriate solvent, filter and set aside.
2. Chemical synthesis steps
(1) Condensation reaction: Add the 13 amino acids dissolved in the first step dropwise to the catalyst, control the temperature and time, and proceed with the condensation reaction. After the reaction is complete, wash the reaction product several times with distilled water until the washing solution does not show acidity.
(2) Hydrolysis reaction: The product of the condensation reaction is added to boiling water for hydrolysis reaction. During the hydrolysis process, it is necessary to control the temperature and time to ensure complete reaction. After completion, filter the hydrolysis product into a dryer and cool it to room temperature for later use.
(3) Recrystallization: Recrystallize the hydrolysis product with an appropriate amount of ethanol to obtain the crude product. Then, further purification was performed using column chromatography to obtain high-purity dynorphin A (1-13).
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