- Preparation of bivalent agonists for targeting the mu opioid and cannabinoid receptors
-
In order to obtain novel pharmacological tools and to investigate a multitargeting analgesic strategy, the CB1 and CB2 cannabinoid receptor agonist JWH-018 was conjugated with the opiate analgesic oxycodone or with an enkephalin related tetrapeptide. The opioid and cannabinoid pharmacophores were coupled via spacers of different length and chemical structure. In vitro radioligand binding experiments confirmed that the resulting bivalent compounds bound both to the opioid and to the cannabinoid receptors with moderate to high affinity. The highest affinity bivalent derivatives 11 and 19 exhibited agonist properties in [35S]GTPγS binding assays. These compounds activated MOR and CB (11 mainly CB2, whereas 19 mainly CB1) receptor-mediated signaling, as it was revealed by experiments using receptor specific antagonists. In rats both 11 and 19 exhibited antiallodynic effect similar to the parent drugs in 20 μg dose at spinal level. These results support the strategy of multitargeting G-protein coupled receptors to develop lead compounds with antinociceptive properties.
- Dvorácskó, Szabolcs,Keresztes, Attila,Mollica, Adriano,Stefanucci, Azzurra,Macedonio, Giorgia,Pieretti, Stefano,Zádor, Ferenc,Walter, Fruzsina R.,Deli, Mária A.,Kékesi, Gabriella,Bánki, László,Tuboly, Gábor,Horváth, Gy?ngyi,T?mb?ly, Csaba
-
-
Read Online
- Concise Synthesis of Potential 4-Hydroxy-5-fluoropentyl Side-Chain Metabolites of Four Synthetic Cannabinoids
-
Synthetic cannabinoids are a group of compounds that act on the CB1 receptor and are used illicitly as substitutes for cannabis. Given the rapid and extensive metabolism of synthetic cannabinoids, urinary biomarkers are essential if proof of drug intake is to be obtained in forensic laboratories. To identify good biomarker candidates, the metabolism of synthetic cannabinoids must be studied and reference standards need to be acquired. Studies on the metabolism of synthetic cannabinoids containing a terminally fluorinated pentyl side chain have shown that hydroxylation can occur at the four position of the side chain. This makes the 4-hydroxy-5-fluoropentyl side-chain metabolite a good urinary biomarker for proving intake of the corresponding parent drug, as this compound cannot be formed from its nonfluorinated analogue. Here, a concise synthetic route to the 4-hydroxy-5-fluoropentyl side-chain metabolites of the synthetic cannabinoids STS-135, MAM-2201, AM-2201, and XLR-11 is reported.
- Dahlén, Johan,Konradsson, Peter,Liu, Huiling,Rexander, Anders,Vestling, Erik,Wallgren, Jakob,Wu, Xiongyu
-
-
Read Online
- Methodology for controlled administration of smoked synthetic cannabinoids JWH-018 and JWH-073
-
Synthetic cannabinoids (SCs) are a significant public health concern given their widespread use and severe effects associated with intoxication. However, there is a paucity of controlled human studies investigating the behavioral and physiological effects and pharmacokinetics of these compounds. Designing a reliable method to administer consistent, concentration-dependent synthetic cannabinoids is an integral component of controlled study of these compounds. Further, optimizing methods to assess the parent compounds and metabolites in plasma is critical in order to be able to establish their pharmacokinetics after administration. To develop a reliable method to administer smokable, concentration-dependent SCs, cigarettes were prepared with plant matter adulterated with increasing concentrations of the first generation cannabinoids found in SC products, JWH-018 and JWH-073. Cigarettes were assessed 1–6 months after preparation using ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) to determine compound stability over time and concentration consistency throughout the cigarettes. Optimal conditions to detect metabolites in human plasma as a function of storage temperature (?4 °C to ?80 °C) and time (24 h - 1 month) were also determined. Analyses verified that the method utilized to develop SC cigarettes yielded consistent, concentration-dependent products within 25% of the expected concentrations. JWH-018, JWH-073 and metabolites in spiked plasma were stable under the time and temperature conditions; concentrations were within ±20% of target values. These studies provide techniques and methods to conduct controlled investigations of the dose-dependent effects of first generation SCs to begin understanding risks associated with use. This article is part of the Special Issue entitled ‘Designer Drugs and Legal Highs.’
- Cooper, Ziva D.,Poklis, Justin L.,Liu, Fei
-
-
Read Online
- Synthesis of 3-acylindoles: via copper-mediated oxidative decarbethoxylation of ethyl arylacetates
-
An efficient regioselective C-3 acylation of free indoles (N-H) has been accomplished via oxidative decarbethoxylation of easily available ethyl arylacetates using Cu(OAc)2 and KOtBu in DMSO.
- Jaiswal, Anjali,Sharma, Anup Kumar,Singh, Krishna Nand
-
supporting information
p. 1623 - 1628
(2020/03/06)
-
- A novel synthesis of N-hydroxy-3-aroylindoles and 3-aroylindoles
-
A straightforward indole synthesis via annulation of C-nitrosoaromatics with conjugated terminal alkynones was realised achieving a simple, highly regioselective, atom- and step economical access to 3-aroylindoles in moderate to good yields. Further functionalizations of indole scaffolds were investigated and an easy way to JWH-018, a synthetic cannabinoid, was achieved.
- Ieronimo, Gabriella,Palmisano, Giovanni,Maspero, Angelo,Marzorati, Alessandro,Scapinello, Luca,Masciocchi, Norberto,Cravotto, Giancarlo,Barge, Alessandro,Simonetti, Marco,Ameta, Keshav Lalit,Nicholas, Kenneth M.,Penoni, Andrea
-
p. 6853 - 6859
(2018/10/20)
-
- Compound
-
PROBLEM TO BE SOLVED: To solve the problems that the sensibility of prior arts such as GC-MC and LC-MS is within an order of ppm, further that the sensibility is substantially reduced if there are impurities, and that the measurement takes a long time (not less than 30 minutes) as a result since a certain amount of impurities have to be removed for a preliminary treatment. SOLUTION: A hapten useful for producing an antibody specific to a synthetic cannabinoid is a compound having a structure represented by a structural formula (1). An immunogen can be easily obtained by linking the compound with keyhole limpet hemocyanin which is a carrier protein. The immunogen is immunized for an animal to produce a specific antibody. SELECTED DRAWING: Figure 1 COPYRIGHT: (C)2016,JPOandINPIT
- -
-
Paragraph 0014; 0015
(2017/06/24)
-
- Detection of synthetic cannabinoids
-
The invention describes methods and kits for detecting and determining current and future synthetic cannabinoids from the JWH and CP families. Unique antibodies derived from immunogens enable said methods and kits.
- -
-
Page/Page column
(2014/03/22)
-
- A novel microwave-irradiated solvent-free 3-acylation of indoles on alumina
-
A simple and efficient 3-acylation of indoles under microwave-heated and solvent-free conditions is developed. This general procedure uses neutral Al2O3 as a new, green and reusable catalyst giving good to high yields within short reaction times. Utilizing such an environmentally- benign methodology, a variety of indoles bearing electron-releasing or electron-withdrawing groups were conveniently acylated.
- Lai, Qiu Yu,Liao, Rong Su,Wu, Shao Yong,Zhang, Jia Xin,Duan, Xin Hong
-
p. 4069 - 4076
(2013/12/04)
-
- Detection of Synthetic Cannabinoids
-
The invention describes methods and kits for detecting and determining current and future synthetic cannabinoids from the JWH and CP families. Unique antibodies derived from novel immunogens enable said methods and kits.
- -
-
Page/Page column 8
(2012/08/28)
-
- Detection of Synthetic Cannabinoids
-
The invention describes methods and kits for detecting and determining current and future synthetic cannabinoids from the JWH and CP families. Unique antibodies derived from novel immunogens enable said methods and kits.
- -
-
-
- Effect of sodium naphthalenide, a key set reagent, on 3-substituted indoles
-
Action of the single electron transfer (SET) reagent sodium naphthalenide on 3-substituted indoles revealed that indoles with electron-donating substituents do not respond whereas indoles with electron-withdrawing substituents easily react, yielding several products depending upon the substituent.
- Banerji, Avijit,Bandyopadhyay, Debasish,Basak, Bidyut
-
p. 2371 - 2377
(2007/10/03)
-
- C-attached aminoalkylindoles: Potent cannabinoid mimetics
-
Aminoalkylindoles (AAIs) with potent cannabinoid agonist activity have been synthesized where the aminoalkyl chain is attached to the indole ring via a carbon atom of the cyclic amine.
- D'Ambra, Thomas E.,Eissenstat, Michael A.,Abt, Jeffrey,Ackerman, James H.,Bacon, Edward R.,Bell, Malcolm R.,Carabateas, Philip M.,Josef, Kurt A.,Kumar, Virendra,Weaver III, John D.,Arnold, Renee,Casiano, Frances M.,Chippari, Susan M.,Haycock, Dean A.,Kuster, Joan E.,Luttinger, Daniel A.,Stevenson, Joan I.,Ward, Susan J.,Hill, W. Adam,Khanolkar, Atmaram,Makriyannis, Alexandros
-
-
- The regioselective photoinduced aroylation at the 3-position of pyrrole derivatives
-
Irradiation of arenecarbothioamide with pyrrole or indole derivatives gave regioselectively 3-aroylpyrrole or -indole derivatives, respectively.
- Oda, Kazuaki,Hiratsuka, Rin,Machida, Minoru
-
p. 463 - 470
(2007/10/03)
-
- 3-arylcarbonyl-1-(C-attached-N-heteryl)-1H-indoles
-
2-R2 -R4 -substituted-3-R3 -CO-1-[(C-attached-N-herteryl)-(Alk)n ]-1H-indoles useful as analgesic, anti-rheumatic, anti-inflammatory or anti-glaucoma agents.
- -
-
-
