NMDA Receptor

In rat cerebral cortical membranes, [3H]dizocilpine maleate binds with NMDA receptors at a Kd of 37.2±2.7 nM[1]. N-Me-D-Asp-induced current blockade is progressive and long-lasting when dizocilpine maleate is used[3]. The NMDA-induced current is gradually suppressed by dizocilpine maleate. Even when Dizocilpine (MK-801) is applied for an extended period of time in the presence of NMDA, Mg2+ (10 mM) inhibits Dizocilpine from blocking the N-Me-D-Asp-induced current. In outside-out patches, dizocilpine inhibits NMDA-activated single-channel activity[3]. Dizocilpine maleate (less than 500 μM) suppresses LPS-induced microglia activation, which is accompanied by elevated Cox-2 protein expression in BV-2 cells. In BV-2 cells, dococilpine (MK-801; <500 μM) decreases microglial TNF-α production with an EC50 of 400 μM[4].

In animal modeling, dizocilpine maleate can be used to create models of schizophrenia. Recent research suggests that drug-related memories are reactivated after exposure to environmental cues and may undergo reconsolidation, a process that can strengthen memories. Conversely, reconsolidation may be disrupted by certain pharmacological agents such that the drug-associated memory is weakened. Several studies have demonstrated disruption of memory reconsolidation using a drug-induced conditioned place preference (CPP) task, but no studies have explored whether cocaine-associated memories can be similarly disrupted in cocaine self-administering animals after a cocaine priming injection, which powerfully reinstates drug-seeking behavior. Here we used cocaine-induced CPP and cocaine self-administration to investigate whether the N-methyl-D-aspartate receptor antagonist (+)-5methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801) given just prior to reactivation sessions would suppress subsequent cocaine-primed reinstatement (disruption of reconsolidation). Systemic injection of MK-801 (0.05 or 0.20 mg/kg administered intraperitoneally) in rats just prior to reactivation of the cocaine-associated memory in the CPP context attenuated subsequent cocaine-primed reinstatement, while no disruption occurred in rats that did not receive reactivation in the CPP context. However, in rats trained to self-administer cocaine, systemic administration of MK-801 just prior to either of two different types of reactivation sessions had no effect on subsequent cocaine-primed reinstatement of lever-pressing behavior. Thus, systemic administration of MK-801 disrupted the reconsolidation of a cocaine-associated memory for CPP but not for self-administration. These findings suggest that cocaine-CPP and self-administration do not use similar neurochemical processes to disrupt reconsolidation or that cocaine-associated memories in self-administering rats do not undergo reconsolidation, as assessed by lever-pressing behavior under cocaine reinstatement conditions [5].

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The effects of five administrations (3- to 4-day intervals) of morphine (MOR: 10 and 20 mg/kg, s.c.) alone, MK-801 (dizocilpine: 0.03, 0.1, 0.3 and 1 mg/kg, i.p.) alone, and combinations of MOR with MK-801 on the ambulation in mice were investigated. MK-801 at 0.3 and 1 mg/kg, but not at 0.03 and 0.1 mg/kg, significantly increased the ambulation of mice. Although the mice given repeated administrations of MK-801 (0.3 and 1 mg/kg) exhibited enhancement and reduction, respectively, in the ambulation-increasing effect of the individual doses, they showed significantly higher sensitivity than the saline-treated mice to the challenge with MOR (10 mg/kg). The repeated administrations of MOR (10 and 20 mg/kg) induced a progressive enhancement of the ambulation-increasing effect. The mice repeatedly given MOR (10 mg/kg) exhibited significant increase in the sensitivity to MK-801 (0.03-0.3 mg/kg). The coadministrations of MOR with MK-801 intensified the ambulation-increasing effect, and repeated coadministrations induced progressive enhancement of the effect, except for the combinations of MOR (10 or 20 mg/kg) with MK-801 (1 mg/kg). However, the induction of MOR sensitization was not modified by any doses of MK-801, except for the case of combination of MOR (20 mg/kg) with MK-801 (1 mg/kg) which was highly toxic (i.e., eliciting death or a moribund condition). On the other hand, simultaneous treatment with SCH 23390 (0.05 mg/kg, s.c.) or nemonapride (0.05 mg/kg, s.c.), or 4-hr pretreatment with reserpine (1 mg/kg, s.c.) strongly, and 4-hr pretreatment with alpha-methyl-p-tyrosine (200 mg/kg, i.p.) partially reduced the ambulation-increasing effect of both MOR (10 mg/kg) and MK-801 (0.3 mg/kg). Simultaneous treatment with naloxone (1 mg/kg, sc) selectively reduced the effect of MOR. However, simultaneous treatment with apomorphine (0.1 mg/kg, s.c.) did not modify the effects of either drug. These results suggest that the characteristics of the ambulation-increasing effects of MOR and MK-801 are similar to each other, and that the repeated treatments with MK-801 induce a cross-sensitization to MOR and vice versa[6].

The compound MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-imine maleate)] is a potent anticonvulsant that is active after oral administration and whose mechanism of action is unknown. We have detected high-affinity (Kd = 37.2 +/- 2.7 nM) binding sites for [3H]MK-801 in rat brain membranes. These sites are heat-labile, stereoselective, and regionally specific, with the hippocampus showing the highest density of sites, followed by cerebral cortex, corpus striatum, and medulla-pons. There was no detectable binding in the cerebellum. MK-801 binding sites exhibited a novel pharmacological profile, since none of the major neurotransmitter candidates were active at these sites. The only compounds that were able to compete for [3H]MK-801 binding sites were substances known to block the responses of excitatory amino acids mediated by the N-methyl-D-aspartate (N-Me-D-Asp) receptor subtype. These comprised the dissociative anesthetics phencyclidine and ketamine and the sigma-type opioid N-allylnormetazocine (SKF 10,047). Neurophysiological studies in vitro, using a rat cortical-slice preparation, demonstrated a potent, selective, and noncompetitive antagonistic action of MK-801 on depolarizing responses to N-Me-D-Asp but not to kainate or quisqualate. The potencies of phencyclidine, ketamine, SKF 10,047, and the enantiomers of MK-801 as N-Me-D-Asp antagonists correlated closely (r = 0.99) with their potencies as inhibitors of [3H]MK-801 binding. This suggests that the MK-801 binding sites are associated with N-Me-D-Asp receptors and provides an explanation for the mechanism of action of MK-801 as an anticonvulsant[1].

Neurons were dissociated from the visual cortex of 2- to 6-day-old Long Evans rat pups and grown in culture for 5-43 days as described (21). Currents activated by excit-fory amino acids were measured in the whole-cell and outside-out patch-clamp configurations. Pipettes contained an internal solution (in mM) of 120 cesium methanesulfonate, 5 CsCI, 10 Cs2EGTA, 5 Mg(OH)2, 5 MgATP, 1 Na2GTP, and 10 Hepes (pH adjusted to 7.4 with CsOH). The external solution (in mM) was 160 NaCl, 2 CaC12, and 10 Hepes (pH 7.40). In whole-cell experiments, 300 nM tetrodotoxin and 10 kLM bicuculline methiodide were added to the external solution to suppress spontaneous activity. MK-801, the kind gift of Paul Anderson, was added from stock solutions of 2-50 mM in ethanol, stored at - 20'C. Final concentrations of ethanol were <0.1%. Cells or patches were bathed in control or agonist-containing external solution flowing from one of a linear array of 7-10 microcapillary tubes fed by gravity. Rapid solution changes were made by moving the array of tubes relative to the cell (whole-cell) or by moving the pipette relative to the tubes (patch). All experiments were done at 20-250C[3].

\n\nSystemic injection of Dizocilpine/MK-801 (0.05 or 0.20 mg/kg administered intraperitoneally) in rats just prior to reactivation of the cocaine-associated memory in the CPP context attenuated subsequent cocaine-primed reinstatement, while no disruption occurred in rats that did not receive reactivation in the CPP context. However, in rats trained to self-administer cocaine, systemic administration of MK-801 just prior to either of two different types of reactivation sessions had no effect on subsequent cocaine-primed reinstatement of lever-pressing behavior. Thus, systemic administration of MK-801 disrupted the reconsolidation of a cocaine-associated memory for CPP but not for self-administration. These findings suggest that cocaine-CPP and self-administration do not use similar neurochemical processes to disrupt reconsolidation or that cocaine-associated memories in self-administering rats do not undergo reconsolidation, as assessed by lever-pressing behavior under cocaine reinstatement conditions.[5]

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\n\nSubjects [5]
\nMale Sprague-Dawley and Long-Evans Hooded rats weighing 280–350 g at the start of the experiment were housed in a temperature- and humidity-controlled colony room with a 12-h light/dark cycle (lights on at 6:00 a.m.). Sprague-Dawley rats were used for all CPP studies, and our initial self-administration studies used Long-Evans rats because of their higher general activity levels and thus higher initial lever pressing during acquisition of the self-administration task. However, to ensure that there were no strain differences in the effects of Dizocilpine/MK-801 on self-administration behavior, we also used Sprague-Dawley rats to test the effects of the highest dose of MK-801 compared with Saline vehicle in this strain. No significant differences were found for the effects of MK-801, so the data from both strains were pooled. Animals undergoing self-administration were housed in a 12-h reverse light/dark cycle (lights on at 6:00 p.m.). Experiments were conducted according to the National Institutes of Health Guide for the Care and Use of Laboratory Animals, and experimental protocols were approved by the University Animal Care and Use Committee. Animals were housed two per cage for the CPP studies and individually for the self-administration studies. Food and water were provided ad libitum except for when animals were engaged in experiments.\n

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\nDrug administration [5]
\n \nDizocilpine(+)-MK-801 hydrogen maleate was dissolved in sterile saline for i.p. injection (1 mL/kg). The doses chosen were 0.05 and 0.20 mg/kg, based on previous work by Przybyslawski and Sara (1997).\n

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\nSurgery [5]
\nSelf-administration surgery was conducted according to a modification of McFarland and Kalivas (2001). Rats were anesthetized with zyket (ketamine 87 mg/kg + xylazine 13 mg/kg) given intramuscularly prior to implanting a chronic indwelling i.v. catheter. The catheter was surgically implanted into the right jugular vein, and the distal end was led subcutaneously to the back between the scapulas. Catheters were constructed from Silastic tubing (9 cm; inner diameter 0.025 in, outer diameter 0.047 in) connected to a back-mount cannula pedestal, a bent 22-gauge metal cannula encased within a plastic screw connector attached to a polyester mesh (Plastics One). A small ball of silicone sealant was placed ∼2.8 cm from the end of the catheter. The right jugular vein was isolated, the most anterior portion of the vein was tied shut, and a small incision was made. The distal end of the catheter was inserted into the vein until the silicone ball was flush with the vein. The vein was secured by tying suture thread on both sides of the silicone ball; additionally, the thread on both sides was tied together. Immediately after surgery, the catheter was injected with 0.1 mL of locking solution: heparin (500 U/mL), gentamicin (5 mg/mL), and glycerol (60%) in sterile saline. Incisions were sutured, and the animal was given 5–7 d to recover. After surgery, the catheter was flushed daily with 0.1 mL of heparin (10 U/mL) and gentamicin antibiotic (5 mg/mL) in sterile saline to help protect against infection and catheter occlusion.\n

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\nBehavioral procedures [5]
\nCPP [5]
\nAll CPP studies were conducted during the same time of day. The proposed studies employed a three-compartment CPP apparatus as previously described (Brown et al. 2007). Briefly, the procedure consisted of a preconditioning preference test, training for 8 d (4 saline pairings alternating with 4 cocaine pairings), testing for CPP acquisition followed by extinction sessions, and cocaine-primed reinstatement with a 10 mg/kg, i.p. dose of cocaine (Brown et al. 2007). Except for the training days, rats had access to all three compartments of the CPP apparatus.\n

\nIn Experiment 1, we tested whether Dizocilpine/MK-801 would impair reconsolidation of the memory for the cocaine-associated context during reinstatement testing. Animals underwent preconditioning, conditioning, testing, and extinction as described above, and on Reactivation Day 1, rats received saline or MK-801 (0.05 mg/kg or 0.20 mg/kg, i.p.) 30 min prior to a cocaine injection (10 mg/kg, i.p.) and placed immediately into the central compartment of the CPP box (Reactivation Day 1). Rats were allowed to explore all three compartments. The next day, the procedure from Reactivation Day 1 was repeated (Reactivation Day 2). This procedure was given for 2 d because our previous studies using a different pharmacological agent (Brown et al. 2007) indicated that one day of memory reactivation was not sufficient to disrupt subsequent cocaine-primed reinstatement. The following day, animals were tested for cocaine-primed reinstatement without any prior injection of either saline or MK-801 before being placed into the CPP box (Reinstatement Day). Rats were allowed to explore all three compartments.\n

\nExperiment 2 was identical to Experiment 1 with the exception of the cage location where Dizocilpine/MK-801 and cocaine injection took place on Reactivation Days 1 and 2. In Experiment 2, animals were given saline or MK-801 followed by cocaine 30 min later in the home cage instead of in the CPP apparatus for the two days of “reactivation.” This was done to determine whether reactivation of the memory for the cocaine-associated context by cocaine in the CPP context was necessary for the ability of MK-801 to disrupt reconsolidation. Animals underwent preconditioning, conditioning, testing, and extinction as described above but animals were injected with saline or MK-801 (0.20 mg/kg, i.p.) 30 min prior to a cocaine injection (10 mg/kg, i.p.) in the home cage. Animals remained in the home cages, and the next day, the procedure from the first day of reactivation was repeated. The following day, animals were tested for cocaine-primed reinstatement in their CPP box without any prior microinjection of saline or MK-801, exactly as described for the Reinstatement Day in Experiment 1 above.

Dissolved in saline; 0.1mg/kg; oral gavage

Male Sprague-Dawley rats

Dezocepine (MK-801) is a non-competitive NMDA receptor antagonist with high binding affinity, requiring an open pathway to block the receptor. Key pharmacokinetic characteristics include:
1. Bioavailability and Absorption
o Although specific bioavailability data for dezocepine are not available in the literature, its structural analogue, olphenadrine (an NMDA receptor antagonist with similar properties), has been shown to cross the blood-brain barrier, suggesting that dezocepine may also possess this property.
2. Metabolism and Elimination
o Studies in Reeler mice have shown that the efficacy of dezocepine is associated with GABAergic regulation, suggesting that it may be metabolized in the liver, which is involved in neurotransmitter pathways.
o Comparative pharmacokinetic data from paliperidone derivatives indicate that some drugs targeting the central nervous system may be rapidly metabolized, but the exact metabolic profile of dezocepine remains unclear.
3. Pharmacodynamic Interactions
o In the synaptic plasticity dysfunction model, dezoceppine exhibited enhanced NMDA receptor blocking, suggesting that the pharmacokinetic-pharmacodynamic relationship is context-dependent.
Further data beyond the current search results are needed for precise quantification (e.g., T_max, half-life).

The intravenous LD50 in mice is 30 mg/kg. (US Patent Document #5273989)

[1]. The anticonvulsant MK-801 is a potent N-Me-D-Asp antagonist. Proc Natl Acad Sci U S A. 1986 Sep;83(18):7104-8.

[2]. Convergent Strategy to Dizocilpine MK-801 and Derivatives. J Org Chem. 2018 Apr 6;83(7):4264-4269.

[3]. Block of N-Me-D-Asp-activated current by the anticonvulsant MK-801: selective binding to open channels. Proc Natl Acad Sci U S A. 1988 Feb;85(4):1307-11.

[4]. MK-801 and dextromethorphan block microglial activation and protect against neurotoxicity. Brain Res. 2005 Jul 19;1050(1-2):190-8.

[5]. The NMDA antagonist MK-801 disrupts reconsolidation of a cocaine-associated memory for conditioned place preference but not for self-administration in rats. Learn Mem. 2008 Dec 2;15(12):857-65.

[6]. Modification by MK-801 (dizocilpine), a noncompetitive NMDA receptor antagonist sensitization: evaluation by ambulation in mice. Nihon Shinkei Seishin Yakurigaku Zasshi. 1996 Feb;16(1):11-8.

[7]. Decrease of growth and differentiation factor 10 contributes to neuropathic pain through N-Me-D-Asp receptor activation. Neuroreport. 2017 May 24;28(8):444-450.

Dizocilpine maleate is a maleate salt prepared by reacting dezoceppine with an equivalent amount of maleic acid. It possesses anesthetic, anticonvulsant, neuroprotective, nicotine receptor antagonist, and NMDA receptor antagonist effects. It is a maleate salt and a tetracyclic antidepressant. It contains a dezoceppine (1+) molecule. It is a potent, non-competitive NMDA receptor (N-methyl-D-aspartate receptor) antagonist, primarily used as a research tool. This drug has been considered for the treatment of various neurodegenerative diseases or diseases where NMDA receptors may play an important role. Due to its psychoactive effects, the application of MK-801 is mainly limited to animal and tissue experiments. The compound MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5,10-imine maleate] is a potent anticonvulsant that takes effect after oral administration, but its mechanism of action is not yet fully understood. We detected high-affinity binding sites for [3H]MK-801 in the rat meninges (Kd = 37.2 ± 2.7 nM). These sites exhibited thermal instability, stereoselectivity, and region specificity, with the highest density in the hippocampus, followed by the cerebral cortex, striatum, and medulla-pons. No binding was detected in the cerebellum. The MK-801 binding sites exhibited a novel pharmacological character, as none of the major neurotransmitter candidates responded to these sites. The only compounds that could compete with [3H]MK-801 for binding sites were substances known to block excitatory amino acid responses mediated by N-methyl-D-aspartate (N-Me-D-Asp) receptor subtypes. These substances included the dissociative anesthetics phencyclidine and ketamine, and the sigma-type opioid N-allylnormetazocine (SKF 10,047). In vitro neurophysiological studies (using rat cortical sections) showed that MK-801 exhibits potent, selective, and non-competitive antagonism against the depolarization response of N-Me-D-Asp, but no antagonism against the depolarization response of fumarate or quesquiate. The potency of phencyclidine, ketamine, SKF 10,047, and the MK-801 enantiomers as N-Me-D-Asp receptor antagonists was closely correlated with their potency as [3H]MK-801 binding inhibitors (r = 0.99). This suggests that the MK-801 binding site is associated with the N-Me-D-Asp receptor and provides an explanation for the mechanism of action of MK-801 as an anticonvulsant. [1]

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The effects of the anticonvulsant MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cycloheptene-5,10-imine maleate] on excitatory amino acid responses in cultured rat neocortical neurons were investigated using whole-cell and single-channel recording techniques. MK-801 gradually and persistently blocked N-methyl-D-aspartate (N-Me-D-Asp)-induced currents. However, during the inhibition of the N-Me-D-Asp response, there was no effect on the responses to quisquiate or ruminoidine, suggesting that the N-Me-D-Asp receptor and the ruminoidine/quisquiate receptor activate different ion channel groups. The binding and dissociation of MK-801 appear to occur only when N-Me-D-Asp-activated channels are in a neurotransmitter-activated state: MK-801 is only effective when applied concurrently with N-Me-D-Asp, and sustained exposure to N-Me-D-Asp accelerates the recovery of MK-801 blockade [time constant (τ) approximately 90 minutes at -70 to -80 mV]. Recovery of channel blockade following sustained N-Me-D-Asp application exhibits a significant voltage dependence, with faster recovery at positive potentials (τ approximately 2 minutes at +30 mV). Mg2+ is thought to block N-Me-D-Asp-activated ion channels, and at negative membrane potentials, Mg2+ inhibits the blocking effect of MK-801. In single-channel recordings with the patch-clamp facing outwards, MK-801 significantly reduced N-Me-D-Asp-induced channel activity but did not significantly alter the major single-channel conductance. Consistent with open-channel blocking mechanisms, MK-801 reduced mean channel opening time in a dose-dependent manner. [3]

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In summary, our study is the first to demonstrate that the same activation parameters and drug (MK-801) that interfere with the reconsolidation of cocaine-related memories in a conditioned position preference (CPP) task do not interfere with the reconsolidation of cocaine-related memories in a self-dosing task. Furthermore, the activation parameters of the simulated self-dosing procedure itself (which should therefore promote the effective retrieval of cocaine-related memories) also failed to make the memory susceptible to interference by MK-801. The potential to reduce persistent and unwanted memories by interfering with the reconsolidation process opens up an exciting new field for developing treatments for pathological conditions, including substance abuse. However, the complexities of memory storage and subsequent memory retrieval that could ultimately lead to memory recoding are only beginning to be elucidated, and therefore require further systematic investigation into the timing and specific parameters of reactivation. [5]

C20H19NO4

337.3692

337.131

C, 71.20; H, 5.68; N, 4.15; O, 18.97

77086-22-7

(-)-Dizocilpine maleate;121917-57-5;Dizocilpine;77086-21-6

6420042

White to off-white solid powder

541ºC at 760 mmHg

183-185ºC

281ºC

3.19

3

5

2

25

432

2

C[C@@]12C3=CC=CC=C3C[C@@H](N1)C4=CC=CC=C24.C(=C\C(=O)O)\C(=O)O

QLTXKCWMEZIHBJ-BTJKTKAUSA-N

InChI=1S/C16H15N.C4H4O4/c1-16-13-8-4-2-6-11(13)10-15(17-16)12-7-3-5-9-14(12)16;5-3(6)1-2-4(7)8/h2-9,15,17H,10H2,1H3;1-2H,(H,5,6)(H,7,8)/b;2-1-

5-methyl-10,11-dihydro-5H-5,10-epiminodibenzo[a,d][7]annulene maleate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (7.41 mM) (saturation unknown) in 10% EtOH + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear EtOH stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (7.41 mM) (saturation unknown) in 10% EtOH + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear EtOH stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.19 mg/mL (6.49 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 21.9 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 4: ≥ 2.08 mg/mL (6.17 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 5: ≥ 2.08 mg/mL (6.17 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 6: 3.45 mg/mL (10.23 mM) in Saline (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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 (Please use freshly prepared in vivo formulations for optimal results.)