Schedules of Controlled Substances: Placement of UR-144, XLR11, and AKB48 into Schedule I. Final rule.

With the issuance of this final rule, the Drug Enforcement Administration places (1-pentyl-1H-indol-3-yl)(2,2,3,3-tetramethylcyclopropyl)methanone (UR-144), [1-(5-fluoro-pentyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone (5-fluoro-UR-144, XLR11), and N-(1-adamantyl)-1-pentyl-1H-indazole-3-carboxamide (APINACA, AKB48), including their salts, isomers, and salts of isomers whenever the existence of such salts, isomers, and salts of isomers is possible, into schedule I of the Controlled Substances Act. This scheduling action is pursuant to the Controlled Substances Act which requires that such actions be made on the record after opportunity for a hearing through formal rulemaking. This action imposes the regulatory controls and administrative, civil, and criminal sanctions applicable to schedule I controlled substances on persons who handle (manufacture, distribute, reverse distribute, import, export, engage in research, conduct instructional activities or chemical analysis, or possess), or propose to handle UR-144, XLR11, or AKB48.

Considerations for a Pediatric Biopharmaceutics Classification System (BCS): application to five drugs.

It has been advocated that biopharmaceutic risk assessment should be conducted early in pediatric product development and synchronized with the adult product development program. However, we are unaware of efforts to classify drugs into a Biopharmaceutics Classification System (BCS) framework for pediatric patients. The objective was to classify five drugs into a potential BCS. These five drugs were selected since both oral and intravenous pharmacokinetic data were available for each drug, and covered the four BCS classes in adults. Literature searches for each drug were conducted using Medline and applied to classify drugs with respect to solubility and permeability in pediatric subpopulations. Four pediatric subpopulations were considered: neonates, infants, children, and adolescents. Regarding solubility, dose numbers were calculated using a volume for each subpopulation based on body surface area (BSA) relative to 250 ml for a 1.73 m(2) adult. Dose numbers spanned a range of values, depending upon the pediatric dose formula and subpopulation. Regarding permeability, pharmacokinetic literature data required assumptions and decisions about data collection. Using a devised pediatric BCS framework, there was agreement in adult and pediatric BCS class for two drugs, azithromycin (class 3) and ciprofloxacin (class 4). There was discordance for the three drugs that have high adult permeability since all pediatric permeabilities were low: dolasetron (class 3 in pediatric), ketoprofen (class 4 in pediatric), and voriconazole (class 4 in pediatric). A main contribution of this work is the identification of critical factors required for a pediatric BCS.

The impact of changes in UK classification of the synthetic cannabinoid receptor agonists in 'Spice'.

BACKGROUND: Spice is the iconic brand name of a smokeable herbal mixture containing synthetic cannabinoid receptor agonists. It has been available on the Internet/in head shops in Europe since at least 2006. The synthetic cannabinoid receptor agonist constituents of Spice were classified in the UK as Class B agents in December 2009. This study assessed the impact of this legislation on the synthetic cannabinoid receptor agonists present in Spice products and whether new synthetic cannabinoid receptor agonists outside of the legislation are now available. METHODS: Spice products were bought, prior to and after the change in the UK legislation, from a range of Internet legal high websites selling to UK consumers. Products were analysed using liquid chromatography high-resolution tandem mass spectrometry (LCMSMS). Identification of the synthetic cannabinoid receptor agonist(s) detected was made by comparison to existing databases or by 'in silico' methods. RESULTS: Sixteen products were purchased prior to the UK control of synthetic cannabinoid receptor agonists; all contained at least one synthetic cannabinoid receptor agonist. 20 products were purchased after the UK control; no active compounds were detected in 3 (15%). The remaining 17 (85%) all contained at least one classified synthetic cannabinoid receptor agonist. Additionally, 2 synthetic cannabinoid receptor agonists not covered under current UK generic legislation (AM-694 and the 'novel Belarus compound') were detected. CONCLUSION: Despite the UK 'Spice' classification, classified synthetic cannabinoid receptor agonists continue to be supplied over the Internet to UK users. Furthermore, new synthetic cannabinoid receptor agonists not covered by the legislation are appearing. Consideration needs to be given to reviewing the UK legislation so that suppliers cannot circumvent it by supplying legal alternatives to the classified synthetic cannabinoid receptor agonists.

Headspace volatile composition of the flowers of Caralluma europaea N.E.Br. (Apocynaceae).

The volatile constituents of the flowers of Caralluma europaea (Guss.) N.E.Br (Apocynaceae) from Lampedusa Island were analyzed by a headspace GC method. The analyses allowed the identification and quantification of 41 compounds. The main components were, among the monoterpenoids, terpinolene (23.3%), alpha-terpinene (19.1%) and linalool (18.4%), whereas, among the carbonylic compounds the major constituents were heptanal (2.0%), octanoic acid (2.4%) and hexanoic acid (1.7%). The presence of a nitrogen containing compound, indole (0.8%) and of a sulphur containing compound, dimethylsulphide (t), noteworthy. The compounds found in the flowers of C. europaea have been compared with data available in the literature as regard to their odor, presence in other sapromyiophilous taxa, possible role as semiochemicals, and presence in decaying organic matter. 89.3% of total constituents have been described in other sapromyiophilous taxa. Some of the compounds are present in several types of decaying organic matter (excrements, decomposing bodies, and spoiled fish, etc). Several volatiles found in C. europaea flowers are used as semiochemicals by Hymenoptera, Coleoptera, Diptera, Lepidoptera and other insects. Sixteen volatiles, accounting for 32.4% of the total constituents, are described as attractants of some Diptera families, with a biology linked to decaying organic matter. Our data thus confirm that C. europaea floral bouquet falls within the sapromyiophilous pollination syndrome.

Characterization of two classes of small molecule inhibitors of Arp2/3 complex.

Polymerization of actin filaments directed by the actin-related protein (Arp)2/3 complex supports many types of cellular movements. However, questions remain regarding the relative contributions of Arp2/3 complex versus other mechanisms of actin filament nucleation to processes such as path finding by neuronal growth cones; this is because of the lack of simple methods to inhibit Arp2/3 complex reversibly in living cells. Here we describe two classes of small molecules that bind to different sites on the Arp2/3 complex and inhibit its ability to nucleate actin filaments. CK-0944636 binds between Arp2 and Arp3, where it appears to block movement of Arp2 and Arp3 into their active conformation. CK-0993548 inserts into the hydrophobic core of Arp3 and alters its conformation. Both classes of compounds inhibit formation of actin filament comet tails by Listeria and podosomes by monocytes. Two inhibitors with different mechanisms of action provide a powerful approach for studying the Arp2/3 complex in living cells.

Nitrile glucosides and serotobenine from Campylospermum glaucum and Ouratea turnarea.

Two nitrile glucosides (1S,3S,4S,5R)-4-benzoyloxy-2-cyanomethylene-3,5-dihydroxycyclohexyl-1-O-beta-glucopyranoside (campyloside A) and (1S,3S,4S,5R)-5-benzoyloxy-2-cyanomethylene-3-hydroxy-4-(2-pyrrolcarboxyloxy)cyclohexyl-1-O-beta-glucopyranoside (campyloside B) were isolated from the stem roots of Campylospermum glaucum, whereas serotobenine was isolated from Ouratea turnarea. The structure elucidations were based on spectroscopic evidence. The biological assays of compounds and crude extract of plant species showed good antimicrobial activity of crude extracts against Gram-positive cocci.

Discovery of a new class of potent, selective, and orally bioavailable CRTH2 (DP2) receptor antagonists for the treatment of allergic inflammatory diseases.

A novel chemical class of potent chemoattractant receptor-homologous expressed on Th2 lymphocytes (CRTH2 or DP2) antagonists is reported. An initial and moderately potent spiro-indolinone compound ( 5) was found during a high-throughput screening campaign. Structure-activity relationship (SAR) investigation around the carboxylic acid group revealed that changes in this part of the molecule could lead to a reversal of functional activity, yielding weakly potent agonists. SAR investigation of the succinimide functional group led to the discovery of several single-digit nanomolar antagonists. The potency of these compounds was confirmed in a human eosinophil chemotaxis assay. Moreover, compounds ( R)- 58 and ( R)- 71 were shown to possess pharmacokinetic properties suitable for development as an orally bioavailable drug.

Bisindolylmaleimides with large Stokes shift and long-lasting chemiluminescence properties.

Various bisindolylmaleimides have fluorescence emission maxima wavelengths longer than 500 nm, large Stokes shifts longer than 200 nm, different fluorescence emission wavelengths at an excitation wavelength of 365 nm, and a long-lasting chemiluminescence. The expansion of the pi-conjugation, the pi-bond electronic structure, and oxidation of the C=C bond at the 2,3-position of the maleimide moiety are crucial for producing these fluorescence and chemiluminescence properties.

Total synthesis of marine sponge bis(indole) alkaloids of the topsentin class.

The synthesis of four natural bis(indole) alkaloids of topsentin class 1 and 2 is described. Their bis(indole) alpha-carbonylimidazoline and subsequently bis(indole) alpha-carbonylimidazole moieties have been built via the condensation between indolic alpha-ketothioimidate salts 4 and 1-(indol-3'-yl)-1,2-diaminoethane 3. This compound results from the beta-amino indolic hydroxylamine 5 by a two-step sequence. This is the first total synthesis of compounds 1d, 2a, and 2b.

Bisindole alkaloids of the topsentin and hamacanthin classes from a marine sponge Spongosorites sp.

Seven new (1 and 3-8) and seven known (2 and 9-14) bisindole alkaloids of the topsentin and hamacanthin classes were isolated from the MeOH extract of a marine sponge Spongosorites sp. by bioactivity-guided fractionation. The structure of compound 7 is a revision from our previous report. The planar structures were established on the basis of NMR and MS spectroscopic analyses. Configurations of these compounds were defined by NMR spectroscopy and optical rotation. It is noteworthy that both R and S isomers were isolated for the hamacanthins (1-4, 9, 10, 15, and 16), while a single stereoisomer was isolated for dihydrohamacanthins (5, 11-14, 17, and 18). Compounds 1-4, 6, and 8-14 showed marginal cytotoxicity against five human solid tumor cell lines, and compound 2 showed weak antibacterial activity against clinically isolated methicillin-resistant strains.

Synthesis and antiproliferative activity of substituted benzopyranoisoindoles: a new class of cytotoxic compounds.

A series of novel aminosubstituted benzopyranoisoindoles possessing structural analogy to an active nitracrine metabolite are reported. The compounds exhibited interesting cytotoxic activity against a panel of cell lines, which was maximized by the presence of both 1-dialkylaminoethyl and 3-nitro substituents.

Interaction of the indole class of vacuolar H(+)-ATPase inhibitors with lipid bilayers.

The selective inhibitor of osteoclastic V-ATPase (2Z,4E)-5-(5,6-dichloro-2-indolyl)-2-methoxy-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)-2,4-pentadienamide (SB 242784), member of the indole class of V-ATPase inhibitors, is expected to target the membrane-bound domain of the enzyme. A structural study of the interaction of this inhibitor with the lipidic environment is an essential step in the understanding of the mechanism of inhibition. In this work, a comprehensive study of the relevant features of this interaction was performed. Inhibitor partition coefficients to lipid vesicles as well as its transverse location, orientation (order parameters), and dynamics while bound to bilayers were determined through photophysical techniques, taking advantage of the intrinsic fluorescence of the molecule. To better evaluate the functionally relevant features of SB 242784, a second inhibitor, INH-1, from the same class and having a reduced activity was also examined. It is shown that regarding membrane interaction their properties remain very similar for both molecules, suggesting that the differences in inhibition efficiencies are solely a consequence of the molecular recognition processes within the inhibition site in the V-ATPase.

Antibacterial activity of (-)-deoxypseudophrynaminol versus its racemate and derivatives.

(-)-Deoxypseudophrynaminol 1 possesses 43-fold greater antibacterial potency than the racemate toward Staphylococcus aureus, indicating that the (-)-enantiomer is the biologically active isomer in this assay. Comparison of the percent growth inhibition by derivatives of 1 indicates that prenylation of N8 and replacement of N1-methyl by methyl carbamate are detrimental to antibacterial potency. (-)-1 is a promising lead structure for the development of the novel hexahydropyrrolo[2,3-b]indole class of antibacterial agents.

The landscape after PEACE: do all ACE inhibitors act in an identical way?

The results of the Prevention of Events with Angiotensin Converting Enzyme Inhibition (PEACE trial), involving patients with stable coronary heart disease, demonstrated that the angiotensin-converting enzyme (ACE) inhibitor trandolapril did not reduce cardiovascular mortality, or the incidence of fatal or non-fatal myocardial infarction. These results were in conflict with the vast majority of previously published large-scale trials, and could be seen to weaken confidence in ACE inhibitor therapy of ischaemic heart disease. This review article examines the results of PEACE in comparison with the other major trials in terms of the severity of the disease in the patients, the statistical power of the analyses, the doses of the agents used and the concept of a 'class effect' of the ACE inhibitors.

Isolation and characterization of yuremamine, a new phytoindole.

Yuremamine was isolated and characterized from the stem bark of Mimosa tenuiflora. This plant is still used by indigenous peoples in North-eastern Brazil to make yurema, a psychoactive beverage that is used for medico-religious purpose ( jurema preta or vinho da jurema, in Portuguese). The characterization of this novel compound by NMR and mass spectrometry introduces a new class of phytoindoles.

Synthetic and photochemical studies of substituted 1-acyl-7-nitroindolines.

A previous study of substituent effects on the photo-cleavage of 1-acyl-7-nitroindolines has been extended to examine the effects of electron-donating and electron-withdrawing substituents. 1-Acetyl-4,5-methylenedioxy-7-nitroindoline was inert to 350 nm irradiation, reinforcing an earlier finding that excessive electron-donation by substituents can divert the excited state into non-productive pathways. By contrast, the 1-acetyl-5,7-dinitro- and 1-acetyl-4-methoxy-5,7-dinitroindolines and respectively both showed improved photolysis efficiency in aqueous solution compared to the 1-acyl-4-methoxy-7-nitro compound . Unlike , both and gave mixed photoproducts, the corresponding dinitroindolines and the 5-nitro-7-nitrosoindoles. These results are interpreted in terms of a previous mechanistic study. Investigation of the 4-methoxy-5,7-dinitroindoline conjugate of L-glutamate showed that the stoichiometry of glutamate release upon photolysis was only 65-77% of the theoretical value, suggesting that photolysis of these dinitro compounds may involve pathways other than the clean photolysis previously observed for mono-nitro compounds such as .

1-Pentyl-3-phenylacetylindoles, a new class of cannabimimetic indoles.

A new class of cannabimimetic indoles, with 3-phenylacetyl or substituted 3-phenylacetyl substituents, has been prepared and their affinities for the cannabinoid CB1 and CB2 receptors have been determined. In general those compounds with a 2-substituted phenylacetyl group have good affinity for both receptors. The 4-substituted analogs have little affinity for either receptor, while the 3-substituted compounds are intermediate in their affinities. Two of these compounds, 1-pentyl-3-(2-methylphenylacetyl)indole (JWH-251) and 1-pentyl-3-(3-methoxyphenylacetyl)indole (JWH-302), have 5-fold selectivity for the CB1 receptor with modest affinity for the CB2 receptor. GTPgammaS determinations indicate that both compounds are highly efficacious agonists at the CB1 receptor and partial agonists at the CB2 receptor.

4-(2-Aminoethoxy)-N-(phenylsulfonyl)indoles as novel 5-HT6 receptor ligands.

The preparation of a novel class of 4-(2-aminoethoxy)-N-(phenylsulfonyl)indoles which exhibit high affinity towards the 5-HT6 receptor is reported here. Among these compounds, 4-(2-methylaminoethoxy)-N-(phenylsulfonyl)indole 5g showed superior affinity (Ki = 1 nM) towards the 5-HT6 receptor as well as excellent selectivity (> 2000-fold) against the closely related subtype 5-HT7 receptor.

Class-specific pro-apoptotic effect of statins on human vascular endothelial cells.

Neonangiogenesis represents an important step in tumor development and propagation. Statins may have anticancerogenic potential by blocking vascular endothelial cell growth. The antiproliferative effect of four statins on human endothelial cells was compared, concomitantly delineating a possible pro-apoptotic process. All four statins tested, i. e. atorvastatin, fluvastatin, lovastatin, and simvastatin inhibited cell proliferation. Nearly complete blocking of cell proliferation was achieved at a concentration of 10 microM. We were able to demonstrate that the antiproliferative effect of the statins is not due to cytotoxicity but rather to an apoptotic effect as demonstrated by comparison of cytotoxicity assay and apoptosis assay. The apoptotic mechanism seems to involve caspases, since the statins significantly enhanced caspase activity at dosages of 10 and 20 microM. Further experiments revealed a downregulation of the pro-apoptotic protein Bcl-2. Our data indicate that statins may class-specific inhibit angiogenesis at high dosages which can contribute to prevention of tumor development and progression.

[Third order nonlinear optical properties of three kinds of metal phthalocyanines].

Using YAG laser, the nonlinear optical refractive indexes of three kinds of metal phthalocyanines in DMF, ZnPCS(C6H32N8S4Zn), AlPCS (C56H32AlClN8S4) and AlPCP (C6H32AlClN8O4) were studied with the method of Z-scan. Their third-order susceptibilities chi(3) were also calculated. The result shows that different central ion and different substituents could affect their third-order susceptibilities. The mechanisms of third order optical nonlinearity and energy transfer in the photodynamic therapy were discussed.