Design, synthesis, and preliminary evaluation of a potential synthetic opioid rescue agent.

BACKGROUND: One of the most prominent opioid analgesics in the United States is the high potency agonist fentanyl. It is used in the treatment of acute and chronic pain and as an anesthetic adjuvant. When used inappropriately, however, ingestion of just a few milligrams of fentanyl or other synthetic opioid can cause opioid-induced respiratory depression (OIRD), often leading to death. Currently, the treatment of choice for OIRD is the opioid receptor antagonist naloxone. Recent reports, however, suggest that higher doses or repeated dosing of naloxone (due to recurrence of respiratory depression) may be required to reverse fully fentanyl-induced respiratory depression, rendering this treatment inadequate. To combat this synthetic opioid overdose crisis, this research aims at identifying a novel opioid reversal agent with enhanced efficacy towards fentanyl and other synthetic opioids. METHODS: A series of naltrexone analogues were characterized for their ability to antagonize the effects of fentanyl in vitro utilizing a modified forskolin-induced cAMP accumulation assay. Lead analogue 29 was chosen to undergo further PK studies, followed by in vivo pharmacological analysis to determine its ability to antagonize opioid-induced antinociception in the hot plate assay. RESULTS: A series of potent MOR antagonists were identified, including the highly potent analogue 29 (IC50 = 2.06 nM). Follow-up PK studies revealed 29 to possess near 100% bioavailability following IP administration. Brain concentrations of 29 surpassed plasma concentrations, with an apparent terminal half-life of ~ 80 min in mice. In the hot plate assay, 29 dose-dependently (0.01-0.1 mg/kg; IP) and fully antagonized the antinociception induced by oxycodone (5.6 mg/kg; IP). Furthermore, the dose of 29 that is fully effective in preventing oxycodone-induced antinociception (0.1 mg/kg) was ineffective against locomotor deficits caused by the KOR agonist U50,488. CONCLUSIONS: Methods have been developed that have utility to identify enhanced rescue agents for the treatment of OIRD. Analogue 29, possessing potent MOR antagonist activity in vitro and in vivo, provides a promising lead in our search for an enhanced synthetic opioid rescue agent.

Selective molecular separation of lignin model compounds by reduced graphene oxide membranes from solvent-water mixture.

Selective separation of lignin depolymerization products is key to fractionating and isolating high-value aromatic compounds from the depolymerization process. The primary aim of this study was to synthesis graphene oxide (GO) membranes for selective separations of lignin oligomeric units from polar organic solvent-water media. GO membranes were synthesized on a polymeric substrate by a shear assisted casting of aqueous GO dispersion using a wire-wound rod. Deposited GO was then reduced to different extents by controlled thermal incubation, and the impact on membrane performance was investigated. The extent of reduction of GO was established by extensive characterization with FTIR, XPS, Raman Spectroscopy, XRD, and contact angle measurements. Impressive performance with the rejection of over 70% for the model compound trimer BMP (2,6-bis[(2-hydroxy-5-methyl phenyl) methyl]-4-methylphenol) was achieved compared to only 20% rejection for the dimer GGE (guaiacylglycerol-ß-guaiacylether) with isopropanol-water (90-10% by volume) as a solvent. This corresponds to an encouraging selective separation with selective permeation of dimer (GGE) 3.5 times higher compared to trimer (BMP). rGO membranes exhibited a stable performance over 84 h of operation at a shear rate of 1.1 Pa in a cross-flow mode of operation. Selective separation of GO can be effectively modulated by controlling the O/C ratio by the extent of reduction of GO; indeed, the retention of trimeric compounds increased with increasing GO reduction. The remarkable performance of GO membranes could enable energy-efficient fractionation of lignin oligomeric compounds from polar organic solvents.

Immunoassay testing for barbiturates using alternative matrices in postmortem tissues from cats and dogs.

The barbiturate drug pentobarbital is commonly used by veterinarians for the euthanasia of domestic animals. During the veterinary forensic autopsy, it is sometimes necessary to determine whether the animal was chemically euthanized with pentobarbital. The use of a human immunochromatographic test for barbiturate screening utilizing dog or cat urine has been previously validated; however, the use of alternative matrices for this purpose is yet to be explored when urine is not available. Postmortem heart, liver, spleen, skeletal muscle, blood and/or urine samples from 20 dogs and 26 cats with a reported chemical euthanasia status were processed using two different methods, bead homogenization and sonication, and screened for barbiturates using a human immunochromatographic test. There was 100% agreement of the immunochromatographic test results using the sonication method with the reported euthanasia status of both dogs and cats. Using the bead homogenization method, agreement with the reported euthanasia status was 93.3% and 96.7% for dogs and cats, respectively, due to invalid test results from four dog and two cat samples. A subset of liver samples (10 canine and 10 feline) was analyzed via gas chromatography-mass spectrometry, and there was 100% agreement between the immunochromatographic test results and gas chromatography-mass spectrometry results for both cats and dogs. Overall, our results support the use of a variety of alternative matrices for barbiturate screening in cats and dogs.

Studies of the di-iron(VI) Intermediate in ferrate-dependent oxygen evolution from water.

Molecular oxygen is produced from water via the following reaction of potassium ferrate (K(2)FeO(4)) in acidic solution: 4[H(3)Fe(VI)O(4)](+) + 8H(3)O(+) → 4Fe(3+) + 3O(2) + 18H(2)O. This study focuses upon the mechanism by which the O-O bond is formed. Stopped-flow kinetics at variable acidities in H(2)O and D(2)O are used to complement the analysis of competitive oxygen-18 kinetic isotope effects ((18)O KIEs) upon consumption of natural abundance water. The derived (18)O KIEs provide insights concerning the identity of the transition state. Water attack (WA) and oxo-coupling (OC) transition states were evaluated for various reactions of monomeric and dimeric ferrates using a calibrated density functional theory protocol. Vibrational frequencies from optimized isotopic structures are used here to predict (18)O KIEs for comparison to experimental values determined using an established competitive isotope-fractionation method. The high level of agreement between experimental and theoretic isotope effects points to an intramolecular OC mechanism within a di-iron(VI) intermediate, consistent with the analysis of the reaction kinetics. Alternative mechanisms are excluded based on insurmountably high free energy barriers and disagreement with calculated (18)O KIEs.

Microwave-promoted catalyst- and solvent-free aza-Diels-Alder reaction of aldimines with 6-[2-(dimethylamino)vinyl]-1,3-dimethyluracil.

A microwave-promoted aza-Diels-Alder reaction between 6-[2-(dimethylamino)vinyl]-1,3-dimethyluracil and aldimines has been developed for the construction of dihydropyrido[4,3-d]pyrimidines. Urea is effectively employed as an environmentally benign source of ammonia in the absence of any catalyst or solvent. The key step in the reaction is in situ generation and trapping of the reactive aldimine formed from urea and aldehyde by the diene system of the uracil. The reaction is clean, and excellent yields are obtained in a matter of a few minutes.

Unexpected deviation from diene behaviour of uracil amidine: towards synthesis of some pyrido[2,3-d]pyrimidine derivatives.

Condensation products obtained from the treatment of uracil amidine with preformed or in situ generated suitably substituted olefins unexpectedly undergo intramolecular cyclisation during silica gel chromatography to generate pyrido[2,3-d]pyrimidines. Various reaction conditions are studied and the altered nature of the uracil amidine molecule is further explored by reacting it with different suitably substituted alkenes.

Design, synthesis and biological evaluation of novel scaffold benzo[4,5]imidazo [1,2-a]pyrazin-1-amine: Towards adenosine A2A receptor (A2A AR) antagonist.

Antagonists of adenosine receptor are under exploration as potential drug candidates for treatment of neurological disorders, depression, certain cancers and potentially used as a cancer immunotherapy. Herein, we describe design and synthesis of novel scaffold benzo[4,5]imidazo [1,2-a]pyrazin-1-amine (6) derivatives. All the compounds were evaluated for A2A AR antagonist activity and displayed encouraging results (IC50 9-300 nM) of A2A AR antagonist binding affinity in biochemical assay. Compound 27 exhibits good activity in A2A AR antagonist cAMP functional assay (IC50 31 nM) and further this compound shows T-cell activation at the IL-2 production assay (EC50 165 nM). Molecular docking studies were carried out to rationalize the observed binding affinity of compound 27.

Aromatic N-oxide bridged copper(II) coordination polymers: Synthesis, characterization and magnetic properties.

The complexes [Cu2(o-NO2-C6H4COO)4(PNO)2] (1), [Cu2(C6H5COO)4(2,2'-BPNO)] n (2), [Cu2(C6H5COO)4(4,4'-BPNO)] n (3), [Cu(p-OH-C6H4COO)2(4,4'-BPNO)2·H2O] n (4), (where PNO = pyridine N-oxide, 2,2'-BPNO = 2,2'-bipyridyl-N,N'-dioxide, 4,4'-BPNO = 4,4'-bipyridyl-N,N'-dioxide) are prepared and characterized and their magnetic properties are studied as a function of temperature. Complex 1 is a discrete dinuclear complex while complexes 2-4 are polymeric of which 2 and 3 have paddle wheel repeating units. Magnetic susceptibility measurements from polycrystalline samples of 1-4 revealed strong antiferromagnetic interactions within the {Cu2}4+ paddle wheel units and no discernible interactions between the units. The complex 5, [Cu(NicoNO)2·2H2O] n ·4nH2O, in which the bridging ligand to the adjacent copper(II) ions is nicotinate N-oxide (NicoNO) the transmitted interaction is very weakly antiferromagnetic.

N,N-diphenylbenzamide.

In the title compound, C(19)H(15)NO, the neutral molecules are held together in the crystal structure by very weak C-H...O interactions, giving rise to a linear chain-like structure. The structure of the molecule has been optimized using density functional theory at the B3LYP/6-31G(d) level and this is compared with the molecular structure in the solid state. The two structures show significant differences in the relative orientations of the aromatic rings, which is interesting for further supramolecular study. Apart from the crystal structure analysis, powder X-ray diffraction, UV-visible and thermogravimetric analyses of the compound have been carried out.

1-Benzyl-sulfanyl-2-[(2-chloro-phen-yl)diazen-yl]benzene.

The title compound, C(19)H(15)ClN(2)S, a divalent organosulfur compound belonging to the class of ortho-mercaptoazo compounds, is non-ionic in nature. The azo group in the mol-ecule is moved away from the S atom to attain the stable trans-azo configuration. Here the S atom is not electron deficient, so no intra-molecular N⋯S inter-action exists. Due to steric reasons, the mol-ecule is non-planar: the chlorophenyl and benzyl rings are oriented at dihedral angles of 3.21 (8) and 78.18 (5)°, respectively, with respect to the thiophenyl ring. There are no hydrogen bonds and the crystal structure is stabilized by van der Waals inter-actions.