Sofiniclin
(Synonyms: ABT 894) 目录号 : GC37662
Sofiniclin (ABT 894) 是nAChR的激动剂，是一种有潜力的非兴奋剂来，可用于注意力缺陷症的研究。
Cas No.:799279-80-4
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Kinase experiment: | Receptor studies with ABT-089 and Sofiniclin are done using rat striatal sections. α6β2* nAChR levels are assayed using 125I-α-conotoxinMII (α-CtxMII) (specific activity, 2200 Ci/mmol). α4β2* nAChRs are measured by determining the binding of 125I-epibatidine (specific activity, 2200 Ci/mmol) in the presence of 100 nM α-CtxMII to block α6β2* nAChRs. After assay, sections are exposed to Kodak MR film. To evaluate binding, optical density readings are converted fmol/mg tissue using 125I-standards. |
Animal experiment: | Monkeys: Once stable dyskinesias develops, the effects of ABT-089 and Sofiniclin are determined on LIDs. For these studies, there are two sets of MPTP-lesioned monkeys, Set A (n = 17) and Set B (n = 16). Set A monkeys have previously been treated with nicotine and/or nAChR drugs, followed by a 10 week ishout period (nAChR drug-primed). Set B monkeys have not received any nAChR drug when ABT-089 treatment is initiated (nAChR drug-naive). Our rationale for the use of these two sets of monkeys is to determine if prior treatment with nAChR drugs altered their ability to decrease LIDs. For both sets, there are 3 experimental groups of monkeys, a vehicle-treated group (n = 6), a nAChR drug-treated group (n = 5 or 6) and a nicotine-treated group (n = 5), as a positive control. The monkeys are assigned to the groups such that there are similar number of males and females, with comparable average LID scores. |
References: [1]. Zhang D, et al. ABT-089 and ABT-894 reduce levodopa-induced dyskinesias in a monkey model of Parkinson's disease. Mov Disord. 2014 Apr;29(4):508-17. | |
Sofiniclin (ABT 894) is an agonist of nicotinic acetylcholine receptor (nAChR), used as a potential non-stimulant treatment for attention-deficit/hyperactivity disorder (ADHD).
Sofiniclin is more potent than ABT-089 at both receptor subtypes, with Ki values of 1.9 nM for 125I-α-conotoxinMII binding and of 1.3 nM for 125I-epibatidine binding[1].
Sofiniclin (0.001 to 0.10 mg/kg, p.o.) produces significant reductions in LIDs compared to vehicle monkey[1]. Sofiniclin (0.1 mg/kg) does not decrease LIDs in monkeys with severe nigrostriatal damage[2].
[1]. Zhang D, et al. ABT-089 and ABT-894 reduce levodopa-induced dyskinesias in a monkey model of Parkinson's disease. Mov Disord. 2014 Apr;29(4):508-17. [2]. Zhang D, ET AL. α7 nicotinic receptor agonists reduce levodopa-induced dyskinesias with severe nigrostriatal damage. Mov Disord. 2015 Dec;30(14):1901-11.
| Cas No. | 799279-80-4 | SDF | |
| 别名 | ABT 894 | ||
| Canonical SMILES | ClC1=C(Cl)C=C(N2C[C@]3([H])CN[C@]3([H])C2)C=N1 | ||
| 分子式 | C10H11Cl2N3 | 分子量 | 244.12 |
| 溶解度 | Soluble in DMSO | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
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1 mg | 5 mg | 10 mg |
| 1 mM | 4.0963 mL | 20.4817 mL | 40.9635 mL |
| 5 mM | 0.8193 mL | 4.0963 mL | 8.1927 mL |
| 10 mM | 0.4096 mL | 2.0482 mL | 4.0963 mL |
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| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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1. 首先保证母液是澄清的；
2.
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3. 以上所有助溶剂都可在 GlpBio 网站选购。
ABT-089 and ABT-894 reduce levodopa-induced dyskinesias in a monkey model of Parkinson's disease
Mov Disord 2014 Apr;29(4):508-17.PMID:24515328DOI:10.1002/mds.25817.
Levodopa-induced dyskinesias (LIDs) are a serious complication of levodopa therapy for Parkinson's disease for which there is little treatment. Accumulating evidence shows that nicotinic acetylcholine receptor (nAChR) drugs decrease LIDs in parkinsonian animals. Here, we examined the effect of two β2 nAChR agonists, ABT-089 and ABT-894, that previously were approved for phase 2 clinical trials for other indications. Two sets of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys were administered levodopa/carbidopa (10 mg/kg and 2.5 mg/kg, respectively) twice daily 5 days a week until they were stably dyskinetic. Each set had a vehicle-treated group, an nAChR agonist-treated group, and a nicotine-treated group as a positive control. Set A monkeys had previously received other nAChR drugs (nAChR drug-primed), whereas Set B monkeys were initially nAChR drug-naive. Both sets were administered the partial agonist ABT-089 (range, 0.01-1.0 mg/kg) orally 5 days a week twice daily 30 minutes before levodopa with each dose given for 1 to 5 weeks. ABT-089 decreased LIDs by 30% to 50% compared with vehicle-treated monkeys. Nicotine reduced LIDs by 70% in a parallel group. After 4 weeks of washout, the effect of the full agonist ABT-894 (range, 0.0001-0.10 mg/kg) was assessed on LIDs in Set A and Set B. ABT-894 reduced LIDs by 70%, similar to nicotine. Both drugs acted equally well at α4β2* and α6β2* nAChRs; however, ABT-089 was 30 to 60 times less potent than ABT-894. Tolerance did not develop for the time periods tested (range, 3-4 months). The nAChR drugs did not worsen parkinsonism or cognitive ability. Emesis, a common problem with nAChR drugs, was not observed. ABT-894 and ABT-089 appear to be good candidate nAChR drugs for the management of LIDs in Parkinson's disease.
Metabolism and disposition of ABT-894, a novel α4β2 neuronal acetylcholine receptor agonist, in mice and monkeys
Xenobiotica 2014 Jun;44(6):531-40.PMID:24479584DOI:10.3109/00498254.2013.855836.
1. Metabolism and disposition of ABT-894 was investigated in hepatocytes, in mice and monkeys receiving [(14)C]ABT-894. 2. In hepatocytes, turnover rate of ABT-894 was slow in all species with more than 90% of parent remaining. M3 (carbamoyl glucuronide) and M6 (mono-oxidation) were detected across species. 3. ABT-894 showed species-specific disposition profiles. ABT-894 was primarily eliminated by renal secretion in mice. Whereas, monkey mainly cleared ABT-894 metabolically. 4. ABT-894 underwent two primary routes of metabolism in monkeys: N-carbamoyl glucuronidation to form M3 and oxidation product M1. M3 was the major metabolite in monkey excreta. M3 was observed in mice urine. Circulating levels of M3 in terms of M3/ABT-894 ratios were essentially absent in mice, but were high in monkeys. 5. Understanding the species difference in the clearance mechanism is the key to the accurate projection of the human clearance and preclinical safety assessment. Lack of species difference in the metabolism of ABT-894 in hepatocytes certainly creates a challenge in predicting its metabolism and pharmacokinetics in human. Based on available metabolism and pharmacokinetic data of ABT-894 in human, monkey is the preferred species in predicting human clearance since it presents a similar clearance mechanism from that observed in human.
Different Drugs for the Treatment of Painful Diabetic Peripheral Neuropathy: A Meta-Analysis
Front Neurol 2021 Oct 29;12:682244.PMID:34777192DOI:10.3389/fneur.2021.682244.
Objective: To systematically evaluate the effects of different drugs for the treatment of painful diabetic peripheral neuropathy. Methods: All literature from PubMed, Embase, and Cochrane Central Register of Controlled Trials published over the past 12 years (from January 1, 2008 to June 1, 2020) was searched, and two reviewers independently assessed study eligibility, continuous data extraction, independent assessment of bias risk, and graded strength of evidence. The pain score was used as the main result, and 30 and 50% pain reduction and adverse events were used as secondary results. Results: A total of 37 studies were included. Pregabalin, duloxetine, tapentadol, lacosamide, mirogabalin, and capsaicin were all more effective than placebo in alleviating the pain associated with diabetic peripheral neuropathy, while ABT-894 and gabapentin showed no significant effect. In addition, the efficacy of buprenorphine, tanezumab, fulranumab and others could not be concluded due to insufficient studies. Conclusion: Pregabalin and duloxetine showed good therapeutic effects on painful DPN, but adverse events were also significant. The analgesic effects of ABT-894 and gabapentin need to be further studied with longer and larger RCTs. As an opioid drug, tapentadol has a good analgesic effect, but due to its addiction, it needs to be very cautious in clinical use. Although lacosamide, mirogabalin, and capsaicin are more effective than placebo, the therapeutic effect is weaker than pregabalin. For the results of our meta-analysis, long-term studies are still needed to verify their efficacy and safety in the future. Systematic Review Registration: PROSPERO, identifier: CRD42020197397.
A randomized, double-blind, placebo-controlled phase 2 study of α4β2 agonist ABT-894 in adults with ADHD
Neuropsychopharmacology 2013 Feb;38(3):405-13.PMID:23032073DOI:10.1038/npp.2012.194.
Dysregulation of the neuronal nicotinic acetylcholine receptor (NNR) system has been implicated in attention-deficit/hyperactivity disorder (ADHD), and nicotinic agonists improve attention across preclinical species and humans. Hence, a randomized, double-blind, placebo-controlled, crossover study was designed to determine the safety and efficacy of a novel α4β2 NNR agonist (ABT-894 (3-(5,6-dichloro-pyridin-3-yl)-1(S),5 (S)-3,6-diazabicyclo[3.2.0]heptane)) in adults with ADHD. Participants (N=243) were randomized to one of four dose regimens of ABT-894 (1, 2, and 4 mg once daily (QD)) or 4 mg twice daily (BID) or the active comparator atomoxetine (40 mg BID) vs placebo for 28 days. Following a 2-week washout period, participants crossed over to the alternative treatment condition (active or placebo) for an additional 28 days. Primary efficacy was based on an investigator-rated Conners' Adult ADHD Rating Scale (CAARS:Inv) Total score at the end of each 4-week treatment period. Additional secondary outcome measures were assessed. A total of 238 patients were assessed for safety end points, 236 patients were included in the intent-to-treat data set, and 196 were included in the completers data set, which was the prespecified, primary data set for efficacy. Both the 4 mg BID ABT-894 and atomoxetine groups demonstrated significant improvement on the primary outcome compared with placebo. Several secondary outcome measures were also significantly improved with 4 mg BID ABT-894. Overall, ABT-894 was well tolerated at all dose levels. These results provide initial proof of concept for the use of α4β2 agonists in the treatment of adults with ADHD. Further investigation of ABT-894, including higher doses, is therefore warranted.
Efficacy and safety of the α4β2 neuronal nicotinic receptor agonist ABT-894 in patients with diabetic peripheral neuropathic pain
Pain 2012 Apr;153(4):862-868.PMID:22386472DOI:10.1016/j.pain.2012.01.009.
Preclinical and clinical studies suggest that neuronal nicotinic receptor (NNR) agonists may be a novel and effective therapy for numerous painful conditions. Analgesic efficacy and safety of the highly selective α(4)β(2) NNR agonist ABT-894 was evaluated in 2 separate randomized, double-blind, multicenter, placebo-controlled clinical trials in patients with diabetic peripheral neuropathic pain (DPNP). Study 1 (280 patients randomized) tested 1, 2, and 4 mg ABT-894 twice daily compared with placebo and 60 mg duloxetine once per day over 8 weeks of treatment. Study 2 (124 patients randomized) tested 6 mg ABT-894 twice daily vs placebo for 8 weeks. The primary efficacy outcome measure in both studies was the weekly mean of the 24-hour average pain score recorded in each patient's diary. In both trials, none of the ABT-894 dose groups showed efficacy compared with placebo, whereas duloxetine achieved a statistically significant improvement over placebo in Study 1. All dose levels of ABT-894 were well tolerated, and no significant safety issues were identified. These results are in contrast to the outcome of a previously reported study of DPNP using the less selective α(4)β(2) NNR agonist ABT-594, which demonstrated efficacy compared with placebo, albeit with significant tolerability limitations. The failure of the highly selective α(4)β(2) NNR agonist ABT-894 indicates that it may not be possible to define a therapeutic index for this mechanism or that selectively targeting α(4)β(2) NNRs may not be a viable approach to treating neuropathic pain.