Spiradoline
(Synonyms: 螺朵林,U-62066) 目录号 : GC63200
Spiradoline (U-62066) 是一种芳基乙酰胺，是一种选择性 kappa 阿片受体 (κ-opioid receptor, KOR) 激动剂，在豚鼠中的 Ki 为 8.6 nM。Spiradoline 对 μ 和 δ 受体的 Ki 值分别为 252 nM 和 9400 nM。Spiradoline 具有强效的利尿，止痛，抗心律失常，镇咳，神经保护作用，并易于穿过血脑屏障。
Cas No.:87151-85-7
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >98.00%
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- Datasheet
Spiradoline (U-62066), an arylacetamide, is a selective kappa opioid receptor (KOR) agonist with a Ki of 8.6 nM in guinea pig. The Ki values of Spiradoline for μ and δ receptors are 252 nM and 9400 nM, respectively. Spiradoline has potent diuretic, analgesic, antiarrythmic, antitussive, neuroprotective properties and easily penetrates the blood-brain barrier[1][2].
Using the patch-clamp method in isolated rat cardiac myocytes, indicated that Spiradoline (15 to 500 μM) produces its antiarrythmic effect via blockade of sodium channels (and at the higher doses also of potassium currents) in myocardial tissue. Thus, Spiradoline reduces the peak sodium current, increased the decay rate of the transient outward potassium current, and reduced the sustained plateau potassium amplitude[2].
Spiradoline (U-62066; 0.1-0.4 mg/kg; subcutaneous injection; once; Sprague-Dawley rats) treatment dose-dependently reduces social behaviors in non-stressed adults, producing social avoidance at the highest dose tested, while younger animals displays reduced sensitivity to this socially suppressing effect of Spiradoline. In stressed animals, the socially suppressing effects of the Spiradoline are blunted at all ages, with juveniles and adolescents exhibiting increased social preference in response to certain doses of U-62066[1].
[1]. Elena I Varlinskaya, et al. Stress alters social behavior and sensitivity to pharmacological activation of kappa opioid receptors in an age-specific manner in Sprague Dawley rats. Neurobiol Stress. 2018 Sep 11;9:124-132.
[2]. M-L G Wadenberg. A review of the properties of spiradoline: a potent and selective kappa-opioid receptor agonist. CNS Drug Rev. Summer 2003;9(2):187-98.
| Cas No. | 87151-85-7 | SDF | |
| 别名 | 螺朵林,U-62066 | ||
| 分子式 | C22H30Cl2N2O2 | 分子量 | 425.39 |
| 溶解度 | DMSO : 50 mg/mL (117.54 mM; Need ultrasonic) | 储存条件 | |
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| 1 mM | 2.3508 mL | 11.7539 mL | 23.5078 mL |
| 5 mM | 0.4702 mL | 2.3508 mL | 4.7016 mL |
| 10 mM | 0.2351 mL | 1.1754 mL | 2.3508 mL |
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A review of the properties of Spiradoline: a potent and selective kappa-opioid receptor agonist
CNS Drug Rev 2003 Summer;9(2):187-98.PMID:12847558DOI:10.1111/j.1527-3458.2003.tb00248.x.
The selective kappa-opioid receptor agonist Spiradoline mesylate (U62,066E), an arylacetamide, was synthesized with the intention of creating an analgesic that, while still retaining its analgesic properties, would be devoid of the, mainly mu receptor mediated, side effects such as physical dependence and respiratory depression associated with morphine. Spiradoline is highly selective for the kappa receptor with K(i) of 8.6 nM in guinea pig. Examination of the enantiomers of Spiradoline, showed the (-)enantiomer to be responsible for the kappa agonist properties. Spiradoline easily penetrates the blood brain barrier, and does not seem to have any significant active metabolites. In preclinical studies, Spiradoline has a short duration of action with a peak at around 30 min after administration. The analgesic properties of Spiradoline are well documented in mice and rats. Antitussive properties have also been reported in rats. Furthermore, Spiradoline was reported to display effects suggestive of neuroprotective properties in animal models of ischemia. In humans, Spiradoline is a potent diuretic. It also produces significant sedation presumably due to its antihistamine properties. Preclinical studies have shown that Spiradoline reduces blood pressure and heart rate, and has possible antiarrhythmic properties. Clinical studies did not confirm these findings. kappa Receptors inhibit dopaminergic neurotransmission. Spiradoline, given systematically to rats, produces a significant and long lasting decrease in dopamine release, and in locomotor activity. It has also antipsychotic-like effect in animal behavioral tests. At low doses Spiradoline was reported to decrease tics in patients with Tourette's syndrome. Although Spiradoline had promising effects in animal tests of analgesia, and a reasonably good safety profile in preliminary studies, it did not replace morphine as an analgesic. The available clinical data suggest that Spiradoline produces disturbing adverse effects such as diuresis, sedation, and dysphoria at doses lower than those needed for analgesic effects. Thus, future development of spiradoline-like analgesic compounds should preferably focus on reduction of unwanted effects on the central nervous system. Spiradoline, which currently is commercially available for preclinical research, might prove useful in some psychiatric conditions and possibly as a neuroprotective agent.
Discriminative stimulus effects of Spiradoline, a kappa-opioid agonist
Psychopharmacology (Berl) 1991;105(4):447-52.PMID:1663252DOI:10.1007/BF02244362.
This study represents the initial step in assessing the discriminative effects of Spiradoline (U62,066), a potent congener of the selective kappa-opioid agonist, U50,488. Separate groups of rats were trained to discriminate between SC injections of saline and either 3.0 mg/kg Spiradoline or 3.0 mg/kg morphine in a discrete-trial shock-avoidance/escape procedure. Spiradoline-trained rats generalized completely to U50,488 (ED50S for Spiradoline and U50,488 were 0.66 and 8.71 mg/kg, respectively), but selected the choice lever appropriate for saline in generalization tests with graded doses of morphine, phencyclidine, and agonist-antagonist opioids with varying degrees of kappa activity, ethylketocyclazocine, nalorphine, and butorphanol. Morphine-trained rats did not generalize to Spiradoline. Naltrexone (0.01 or 0.1 mg/kg) blocked surmountably the discriminative effects of both Spiradoline and morphine, but was approximately 10-fold less potent against Spiradoline. These results indicate that the discriminative effects of Spiradoline are mediated by kappa-opioid receptors; meaningful mu-opioid and PCP/sigma components of action were not in evidence. The potency and apparent pharmacological selectivity of Spiradoline suggest the potential value of this drug for studying kappa-opioid-mediated stimulus control of behavior.
Analgesic and mechanistic evaluation of Spiradoline, a potent kappa opioid
J Pharmacol Exp Ther 1988 Jul;246(1):259-62.PMID:2839665doi
Spiradoline (a congener of the kappa opioid agonist, U-50488H) was evaluated for analgesic and related activities in rodents. In nine antinociceptive assays utilizing various thermal, pressure and chemical and physical irritants, the potency of Spiradoline ranges from 4.7 to 23 (mean = 13) times that of U-50488H. Naloxone blocks the analgesic effect of Spiradoline. The in vivo naloxone pA2 for this antagonism is much lower than that for the antagonism of morphine and approximates that of U-50488H. The analgesic potency of Spiradoline is greatly reduced in mice made tolerant to U-50488H but not in those made tolerant to morphine. Repeated treatment with Spiradoline does not induce physical dependence as evidenced by a lack of naloxone-precipitated jumping and withdrawal-induced hyperalgesia. In sum, these observations suggest that Spiradoline is a potent kappa agonist analgesic. However, further evaluation of Spiradoline revealed differences between this compound and U-50488H. We have previously shown that the analgesic effect of the latter compound, but not that of morphine, is profoundly antagonized by reserpine or p-chlorophenylalanine. In contrast, Spiradoline is only marginally antagonized by these serotonin-depleting treatments. Evaluation of the enantiomers of Spiradoline revealed that the (-)-enantiomer is more than 30 times as potent as the (+)-enantiomer in analgesic tests. The (-)-enantiomer is similar to U-50488H with regard to antagonism by p-chlorophenylalanine, lack of physical dependence-inducing properties and cross-tolerance. In contrast the (+)-enantiomer induces physical dependence and displays marked cross-tolerance in morphine-tolerant mice.(ABSTRACT TRUNCATED AT 250 WORDS)
Sodium channel-blocking properties of Spiradoline, a kappa receptor agonist, are responsible for its antiarrhythmic action in the rat
J Cardiovasc Pharmacol 1998 Dec;32(6):863-74.PMID:9869491DOI:10.1097/00005344-199812000-00002.
Spiradoline (U-62,066E), a selective kappa (kappa) receptor agonist, was examined for actions on the cardiovascular system and on myocardial ionic currents in rats. We initially characterized cardiac, hemodynamic, and antiarrhythmic actions of Spiradoline in isolated perfused rat hearts and pentobarbital-anesthetized rats. Electrophysiologic studies in isolated myocytes were used to elucidate the mechanism for changes observed in vivo in the ECG, as well as for antiarrhythmic actions against electrical and ischemia-induced arrhythmias. In isolated rat hearts, Spiradoline reduced heart rate and cardiac contractility and increased the PR interval and QRS width of the ECG in a concentration-dependent manner. In anesthetized rats, Spiradoline dose-dependently reduced blood pressure and heart rate and prolonged the PR interval and QRS width. At slightly higher doses, it increased the QaT interval of the ECG. RSh, an index of sodium channel blockade in the rat, also was dose-dependently increased. Electrical stimulation of the left ventricle suggested that Spiradoline may exert its antiarrhythmic action by blockade of myocardial sodium currents. The electrophysiologic actions of Spiradoline on sodium currents, the transient outward (i(to)) and sustained plateau potassium (ik(sus)) currents were studied in isolated cardiac rat myocytes by whole-cell patch-clamp techniques. Spiradoline (15-500 microM) reduced peak sodium current in a rapid, reversible, and concentration-dependent manner; it also increased the rate of decay of I(to) and reduced the amplitude of Ik(sus). At a concentration of 150 microM, Spiradoline produced a 24 +/- 2 mV hyperpolarizing shift in sodium current inactivation kinetics but did not alter activation processes. Spiradoline showed both tonic and frequency-dependent components of sodium current block. Thus Spiradoline produced its antiarrhythmic actions via sodium channel blockade in myocardial tissue, although higher doses also block potassium currents. This combined ion channel-blocking property may be of added clinical benefit in the setting of myocardial ischemia.
Further characterization of the discriminative stimulus effects of Spiradoline
Pharmacol Biochem Behav 2000 Jul;66(3):517-22.PMID:10899364DOI:10.1016/s0091-3057(00)00172-6.
The results of a previous study in rats indicated that Spiradoline has pharmacologically selective discriminative effects that are mediated by kappa-opioid receptors. However, the training dose, 3.0 mg/kg, increased response latencies, suggesting that it was relatively high. The current study was performed to characterize further the discriminative effects of Spiradoline by using a lower training dose, 1.0 mg/kg, and testing a larger number of drugs for generalization with Spiradoline. Rats were trained in a discrete-trial avoidance/escape procedure to discriminate 1.0 mg/kg Spiradoline, SC, from saline in an average of 19.7 sessions; response latencies after saline and Spiradoline were not different from each other. The rats generalized dose dependently and completely to other kappa-opioid agonists that have relatively high efficacy: ethylketocyclazocine, U69,593, and U50,488. They generalized partially to ketocyclazocine, (-)-N-allylnormetazocine, and DuP 747, and not at all to cyclazocine, butorphanol, nalorphine, and pentazocine, discriminable opioids that have relatively low efficacy at kappa-opioid receptors, or to morphine and dextromethorphan, discriminable drugs that do not act at kappa-opioid receptors. The discriminative effects of Spiradoline were unaffected by the mu-opioid antagonist beta-funaltrexamine, but were blocked completely for at least 4 weeks by the kappa-opioid antagonist nor-binaltorphimine. Thus, spiradoline-like stimulus control of behavior remains kappa-opioid selective, and continues to have a high efficacy requirement even at a training dose that does not impair performance.