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High field side launch of lower hybrid current drive (LHCD) has improved accessibility and penetration over low field side launch on DIII-D. Simulations predict single pass absorption under a wide range of plasma conditions. Hard x-ray (HXR) measurement of LHCD generated fast electron bremsstrahlung (50–250 keV) will validate wave propagation and absorption. Emissivity profiles are recovered from one-dimensional inversion of HXR brightness to determine LH damping location, fast electron slowing down time, and some indication of the fast electron energy. The camera will be implemented by populating 32 tangential sightlines of the existing Gamma Ray Imager with Kromek SPEARTM Cadmium Zinc Telluride (CZT) detectors sensitive to 10–1000 keV photons with 10 keV energy resolution. Expected count rates allow for

Laser powder bed fusion (LPBF), also known as selective laser melting, of Glenn Research Copper 84 (GRCop-84), a Cr2Nb (8 at. % Cr, 4 at. % Nb) precipitation-hardened alloy, produces a fully dense,...

Cannabinoid CB1 receptors (CB1Rs) have been major targets in medication development for the treatment of substance use disorders. However, clinical trials with rimonabant, a CB1R antagonist/inverse agonist, failed due to severe side effects. Here, we evaluated the therapeutic potential of PIMSR, a neutral CB1R antagonist lacking an inverse agonist profile, against cocaine’s behavioral effects in experimental animals. We found that systemic administration of PIMSR dose-dependently inhibited cocaine self-administration under fixed-ratio (FR5), but not FR1, reinforcement, shifted the cocaine self-administration dose-response curve downward, decreased incentive motivation to seek cocaine under progressive-ratio reinforcement, and reduced cue-induced reinstatement of cocaine seeking. PIMSR also inhibited oral sucrose self-administration. Importantly, PIMSR alone is neither rewarding nor aversive as assessed by place conditioning. We then used intracranial self-stimulation (ICSS) to explore the possible involvement of the mesolimbic dopamine system in PIMSR’s action. We found that PIMSR dose-dependently attenuated cocaine-enhanced ICSS maintained by electrical stimulation of the medial forebrain bundle in rats. PIMSR itself failed to alter electrical ICSS, but dose-dependently inhibited ICSS maintained by optical stimulation of midbrain dopamine neurons in transgenic DAT-Cre mice, suggesting the involvement of dopamine-dependent mechanisms. Lastly, we examined the CB1R mechanisms underlying PIMSR’s action. We found that PIMSR pretreatment attenuated Δ9-tetrahydrocannabinol (Δ9-THC)- or ACEA (a selective CB1R agonist)-induced reduction in optical ICSS. Together, our findings suggest that the neutral CB1R antagonist PIMSR deserves further research as a promising pharmacotherapeutic for cocaine use disorder.

Recent advances in selective laser melting 3-D printing technology allow additive manufacturing of lower hybrid current drive (LHCD) RF launchers from a new material, Glenn Research Copper 84 (GRCop-84), a Cr2Nb (8 at. % Cr, 4 at. % Nb) precipitation hardened alloy, in configurations unachievable by conventional machining. Cr2Nb crystals pin grain boundaries within the copper matrix resulting in high tensile strength and resistance to annealing at elevated temperatures. Brazing, laser, and electron-beam welding (EBW) techniques are explored for joining a thin-walled GRCop-84 waveguide with zero porosity and minimal internal surface roughness. GRCop-84 wets well with the silver solder, CuSil, and Cusil-ABA brazes, once the durable surface oxide is mechanically removed. GRCop-84 melt pool size and flow during EBW is reduced compared to oxygen-free copper (OFC). Pulsed laser and e-beam welding maintains the Cr2Nb precipitate size; precipitate coarsening occurs in conduction mode e-beam welding.

During 2012-2018, the clandestine manufacture of new psychoactive substances (NPS) designed to circumvent substance control regulations increased exponentially worldwide, with concomitant increase in fatalities. This review focuses on three compound classes identified as synthetic opioids, synthetic amphetamines, and synthetic cannabinoids and highlights the medicinal chemistry precedents utilized by clandestine laboratories to develop new NPS with increased brain penetration, longer duration of action, and greater potency. Chemical approaches to illicit drug abuse treatment options, particularly for opioid use disorder, are also discussed.

Circulating power within a multijunction launcher is both the system’s greatest strength and a fundamental weakness. Although destructive interference of power reflected from the plasma interface at the multijunction results in low return loss to the RF source, the resulting standing wave within the launcher increases peak electric field, thereby placing fundamental limitations on maximum power handling due to the onset of multipactor breakdown. Passive active multijunctions improve impedance matching at low edge densities but suffer reduction in power density and non-optimal directivity due to the sparse array theorem as half of the waveguides are passive elements. An alternative technique of impedance matching a fully active lower hybrid grill to low edge density conditions with internal matching structures within the waveguide apertures is presented. This method of impedance matching reduces circulating power, sensitivity to edge density conditions and ponderomotive effects, and improves both power density and array directivity.

Building on Alcator C-Mod experience and using the emerging technology of high-temperature superconducting magnet, SPARC is designed to be a compact (R0 = 1.65 m), high field (B0 = 12 T) pulsed tokamak to carry out D-T burning experiments and to demonstrate net-gain from fusion energy. Ion cyclotron range of frequency (ICRF) heating is proposed as the sole auxiliary heating method based on its success on Alcator C-Mod as well as TFTR and JET during their D-T operations. Among all the heating methods, ICRF heating is the only practical and proven method that can heat high density and high field plasmas in SPARC for both the pre-tritium operation and D-T operation. The pre-conceptual design (V0) of the ICRF system has 12 four-strap antennas. Each antenna will be powered by two 2-MW transmitters. Total RF source power (f ~ 120 MHz) will be ≥ 50 MW. Because of high edge density, the antenna loading is expected to be similar to that on Alcator C-Mod, resulting in relatively low voltage on the antennas and in the transmission lines. The single-pass-absorption (SPA) of the fast waves is much higher than that on Alcator C-Mod for the same plasma composition. For D-T burning plasmas with a small amount of 3He, combining the 2nd harmonic T heating and minority 3He heating and in some cases, fundamental D heating, will have good absorption under most plasma conditions. There exists a large parameter space in 3He concentration, k|| and RF frequency for reliable heating. To minimize the impact of impurities, we will use the latest techniques in antenna design and operation scheme, including aligning antenna straps to the magnetic field and tailoring antenna spectra. Ferrite tuners will be implemented in the transmission lines for real-time antenna matching during transient events like L-H transitions and ELMs.

5-Aminoimidazole-4-carboxamide-1-β-D-[13 C5 ] ribofuranosyl 5'-monophosphate ([13 C5 ribose] AICAR-PO3 H2 ) (6) has been synthesized from [13 C5 ]adenosine. Incorporation of the mass-label into [13 C5 ribose] AICAR-PO3 H2 provides a useful standard to aid in metabolite identification and quantification in monitoring metabolic pathways. A synthetic route to the 13 C-labeled compound has not been previously reported. Our method employs a hybrid enzymatic, and chemical synthesis approach that applies an enzymatic conversion from adenosine to inosine followed by a ring-cleavage of the protected inosine. A direct phosphorylation of the resulting 2',3'-isopropylidine acadesine (5) was developed to yield the title compound in 99% purity following ion exchange chromatography.

Many malignant cancers, including breast cancer, have a propensity to invade bones, leading to excruciating bone pain. Opioids are the primary analgesics used to alleviate this cancer-induced bone pain (CIBP) but are associated with numerous severe side effects, including enhanced bone degradation, which significantly impairs patients’ quality of life. In contrast, agonists activating only peripheral CB1 receptors (CB1Rs) have been shown to effectively alleviate multiple chronic pain conditions with limited side effects, yet no studies have evaluated their role(s) in CIBP. Here, we demonstrate for the first time that a peripherally selective CB1R agonist can effectively suppress CIBP. Our studies using a syngeneic murine model of CIBP show that both acute and sustained administration of a peripherally restricted CB1R agonist, 4-{2-[−(1E)-1[(4-propylnaphthalen-1-yl)methylidene]-1H-inden-3-yl]ethyl} morpholine (PrNMI), significantly alleviated spontaneous pain behaviors in the animals. This analgesic effect by PrNMI can be reversed by a systemic administration but not spinal injection of SR141716, a selective CB1R antagonist. Additionally, the cancer-induced bone loss in the animals was not exacerbated by a repeated administration of PrNMI. Furthermore, catalepsy and hypothermia, the common side effects induced by cannabinoids, were measured at the supra-therapeutic doses of PrNMI tested. PrNMI induced mild sedation, yet no anxiety nor a decrease in limb movements were detected. Overall, our studies demonstrate that CIBP can be effectively managed by using a peripherally restricted CB1R agonist, PrNMI, without inducing dose-limiting central side effects. Thus, targeting peripheral CB1Rs could be an alternative therapeutic strategy for the treatment of CIBP.

Laser Powder Bed Fusion (L-PBF), also known as Selective Laser MeltingTM (SLMTM), allows additive manufacture of lower hybrid current drive (LHCD) Radio Frequency (RF) launchers from a new material, Glenn Research Copper 84 (GRCop-84), a Cr2Nb (8 at. % Cr, 4 at. % Nb) precipitation hardened alloy, in configurations unachievable with conventional machining. The resolution and geometric limitations are tested to explore the limitations of L-PBF printing of GRCop-84. Printing holes in the vertical and horizontal direction are examined to determine the minimum cooling channel diameter. Internal stress limits the minimum thickness of vertical walls and septa to 1 mm, thinner walls warp during printing. Roughness is minimized on vertical surfaces and increases on both upper and lower surfaces as angle increases. Accuracy within 40 μm is typical on well supported structures.

Laser Powder Bed Fusion (LPBF) of Glenn Research Copper 84 (GRCop-84), a Cr2Nb (8 at. % Cr, 4 at. % Nb) precipitation hardened alloy, produces a fully dense high conductivity alloy with a yield strength of 500 MPa and ultimate tensile strength (UTS) of 740 MPa, superior to other competing copper alloys, and 20% elongation at fracture for material stressed perpendicular to the build direction. The high thermal stability of the Cr2Nb precipitate in the copper matrix reduces coarsening and maintains a 300 MPa yield, 520 MPa UTS and 26% elongation after a 900 °C, 5-h heat treatment, while a 3 h 450 °C heat treatment increases yield to 810 MPa, UTS to 970 MPa with 9% elongation at fracture, for samples stressed perpendicular to the build direction. Tensile strength anisotropy based on print direction was attributed to internal stress and columnar grain formation. Void nucleation during tensile fracture was initiated by brittle fracture of precipitate particles within the copper matrix. Fracture cusps contain matching precipitate fragment geometry on opposing sides located near the cusp center in at least 80% of fracture cusps. An optimal precipitate size of 100 nm is predicted for maximum tensile strength from precipitates on fracture surfaces, while tensile testing with varying heat treatments shows maximum strength with 100 nm and smaller precipitates. Cr2Nb precipitates are shown to transition between polycrystalline and monocrystalline structures at high temperature.

Recent advances in selective laser melting (SLM) 3D printing technology allows additive manufacture of lower hybrid current drive (LHCD) RF launchers from a new material, Glenn Research Copper 84 (GRCop-84), a Cr2Nb (8 at. % Cr, 4 at. % Nb) precipitation hardened alloy, in configurations unachievable with conventional machining. Rough surfaces in additive manufactured components are a limiting factor in RF structures. Surface roughness increases RF losses and impedes conditioning by trapping gas and contaminants that induce arcing by evolving from the surface at high power. SLM printed GRCop-84 is post-processed with mass finishing to reduce surface roughness. Wet blasting, vibratory finishing, and chemical etching remove adhered powder grains from SLM printed GRCop-84. Profilometry and scanning electron microscopy were used to quantify resulting surface quality. Chemical etching is examined to remove zinc contamination from wire electrical discharge machining slag prior to vacuum use. Etch rates in SLM printed GRCop-84 are anisotropic, and etch times should be limited to prevent pitting corresponding to the laser hatch pattern. Vibratory mass finishing and mechanical polishing produced surfaces suitable for low RF loss. Use of chemo-mechanical finishing is recommended for the interior of SLM printed structures.

Recent advances in selective laser melting (SLM) 3D printing technology allow additive manufacture of lower hybrid current drive (LHCD) RF launchers from a new material, Glenn Research Copper 84 (GRCop-84), a Cr2Nb (8 at. % Cr, 4 at. % Nb) precipitation hardened alloy, in configurations unachievable with conventional machining. Tensile strength and thermal conductivity are compared to other competing high conductivity copper alloys for fusion use. Swelling and conductivity at 100 DPA when exposed to the Hanford Fast Flux Test Facility neutron spectrum is predicted in the 1–2 % and 65−70% IACS range, respectively, by comparison to copper alloys with similar precipitate and grain size. Self-similar ion irradiation of a GRCop-84 target at 430 °C to 20 DPA resulted in no noticeable void formation in FIB cross sections or TEM lamella.

The one-carbon carrier of the formate oxidation level derived from the interaction of tetrahydrofolate and formiminoglutamate, which has been tentatively identified as 5-formiminoltetrahydrofolate, has been prepared by chemical synthesis. Treatment of a solution of (6S)-tetrahydrofolate in aqueous base with excess ethyl formimidate in the presence of anti-oxidant under anaerobic conditions afforded a gummy solid which, based on mass spectral analysis, conformed to a monoformimino derivative of tetrahydrofolate. Further physicochemical characterization by validated methods strongly suggested that the product of chemical synthesis was identical to the enzymatically produced material and that it was, in fact, (6S)-5-formiminotetrahydrofolate. Conditions and handling methods toward maintaining the integrity of this highly sensitive compound were identified and are described, as is analytical methodology, useful for research studies using it.

Chemotherapy-induced peripheral neuropathy (CIPN) is a severe and dose-limiting side effect of cancer treatment that affects millions of cancer survivors throughout the world and current treatment options are extremely limited by their side effects. Cannabinoids are highly effective in suppressing pain symptoms of chemotherapy-induced and other peripheral neuropathies but their widespread use is limited by central nervous system (CNS)-mediated side effects. Here, we tested one compound from a series of recently developed synthetic peripherally restricted cannabinoids (PRCBs) in a rat model of cisplatin-induced peripheral neuropathy. Results show that local or systemic administration of 4-{2-[-(1E)-1[(4-propylnaphthalen-1-yl)methylidene]-1H-inden-3-yl]ethyl}morpholine (PrNMI) dose-dependently suppressed CIPN mechanical and cold allodynia. Orally administered PrNMI also dose-dependently suppressed CIPN allodynia symptoms in both male and female rats without any CNS side effects. Co-administration with selective cannabinoid receptor subtype blockers revealed that PrNMI's anti-allodynic effects are mediated by CB1 receptor (CB1R) activation. Expression of CB2Rs was reduced in dorsal root ganglia from CIPN rats, whereas expression of CB1Rs and various endocannabinoid synthesizing and metabolizing enzymes was unaffected. Daily PrNMI treatment of CIPN rats for two weeks showed a lack of appreciable tolerance to PrNMI's anti-allodynic effects. In an operant task which reflects cerebral processing of pain, PrNMI also dose-dependently suppressed CIPN pain behaviors. Our results demonstrate that PRCBs exemplified by PrNMI may represent a viable option for the treatment of CIPN pain symptoms.

The photolabile analogue of the broad-spectrum opioid antagonist naloxone, 3-O-(4,5-dimethoxy-2-nitrophenyl)carboxymethyl naloxone (also referred to as “caged naloxone”, 3-O-(α-carboxy-6-nitroveratryl)naloxone, CNV-NLX), has been found to be a valuable biochemical probe. While the synthesis of CNV-NLX is simple, its characterization is complicated by the fact that it is produced as a mixture of αR,5R,9R,13S,14S and αS,5R,9R,13S,14S diastereomers. Using long-range and heteronuclear NMR correlations, the 1H NMR and 13C NMR resonances of both diastereomers have been fully assigned, confirming the structures. Monitoring of solutions of CNV-NLX in saline buffer, in methanol, and in DMSO has shown CNV-NLX to be stable for over a week under fluorescent laboratory lights at room temperature. Exposure of such solutions to λ 365 nm from a hand-held UV lamp led to the formation of naloxone and CNV-related breakdown products.

Metabolomics analysis depends on the identification and validation of specific metabolites. This task is significantly hampered by the absence of well-characterized reference standards. The one-carbon carrier 10-formyltetrahydrofolate acts as a donor of formyl groups in anabolism where it is a substrate in formyltransferase reactions in purine biosynthesis. It has been reported as an unstable substance and is currently unavailable as a reference standard for metabolomics analysis.The current study was undertaken to provide the metabolomics community thoroughly characterized 10-formyltetrahydrofolate along with analytical methodology and guidelines for its storage and handling.Anaerobic base treatment of 5,10-methenyltetrahydrofolate chloride in the presence of anti-oxidant was utilized to prepare 10-formyltetrahydrofolate.Pure 10-formyltetrahydrofolate has been prepared and physicochemically characterized. Conditions toward maintaining the stability of a solution of the dipotassium salt of 10-formyltetrahydrofolate in solution have been determined.This study describes the facile preparation of pure (90%) 10-formyltetrahydrofolate, its qualitative physicochemical characterization, as well as conditions to enable its use as a reference standard in physiologic samples.

The first observation of rf heating in a reversed field pinch (RFP) using the electron Bernstein wave (EBW) is demonstrated on the Madison Symmetric Torus. Propagation across and heating in a stochastic magnetic field is observed. Novel techniques are required to measure the suprathermal electron tail generated by EBW heating in the presence of intense Ohmic heating. rf-heated electrons directly probe the edge transport properties in the RFP; measured loss rates imply a large noncollisional radial diffusivity.

PIMSR is among the first neutral antagonists for the CB1R and was demonstrated pharmacologically to bind to the CB1R, yet not alter calcium flux. It was further shown computationally to be able to stabilize both the active and inactive states of CB1R revealing the molecular interactions that mechanistically afford the property of neutral antagonism. PIMSR shows dramatic positive effects in reducing weight, food intake, and adiposity as well as in improving glycemic control and lipid homeostasis in high-fat diet-induced obese mice, but also shows increased ALT and liver weight as markers of liver injury with chronic administration. Further, in a separate study, 3-day administration of PIMSR in C57BL/6J mice, hepatic steatosis from an acute administration of high of ethanol was significantly reduced. Also, it partially prevented alcohol-induced increases in ALT, AST, and LDH. The differences in ALT levels in obese and nonobese mice under different test paradigms are unlikely to be due to neutral antagonism itself since other neutral antagonists (AM6545) do not exhibit liver injury. The brain levels of low micromolar would support significant brain CB1 receptor occupancy (re: Ki = 17nM), thus potentially including both CNS and peripheral influences on the observed weight loss. Overall, these studies suggest that marked improvements in aspects of metabolic disease and alcoholic steatosis can be realized with CB1R neutral antagonists and hence warrants the exploration of further members of this class of cannabinoid ligands.

The cannabinoid 1 (CB1) allosteric modulator, 5-chloro-3-ethyl-1H-indole-2-carboxylic acid [2-(4-piperidin-1-yl-phenyl)-ethyl]-amide) (ORG27569), has the paradoxical effect of increasing the equilibrium binding of [3H](−)-3-[2-hydroxyl-4-(1,1-dimethylheptyl)phenyl]-4-[3-hydroxylpropyl]cyclohexan-1-ol (CP55,940, an orthosteric agonist) while at the same time decreasing its efficacy (in G protein-mediated signaling). ORG27569 also decreases basal signaling, acting as an inverse agonist for the G protein-mediated signaling pathway. In ligand displacement assays, ORG27569 can displace the CB1 antagonist/inverse agonist, N-(piperidiny-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide(SR141716A). The goal of this work was to identify the binding site of ORG27569 at CB1. To this end, we used computation, synthesis, mutation, and functional studies to identify the ORG27569-binding site in the CB1 TMH3-6-7 region. This site is consistent with the results of K3.28192A, F3.36200A, W5.43279A, W6.48356A, and F3.25189A mutation studies, which revealed the ORG27569-binding site overlaps with our previously determined binding site of SR141716A but extends extracellularly. Additionally, we identified a key electrostatic interaction between the ORG27569 piperidine ring nitrogen and K3.28192 that is important for ORG27569 to act as an inverse agonist. At this allosteric site, ORG27569 promotes an intermediate conformation of the CB1 receptor, explaining ORG27569's ability to increase equilibrium binding of CP55,940. This site also explains ORG27569's ability to antagonize the efficacy of CP55,940 in three complementary ways. 1) ORG27569 sterically blocks movements of the second extracellular loop that have been linked to receptor activation. 2) ORG27569 sterically blocks a key electrostatic interaction between the third extracellular loop residue Lys-373 and D2.63176. 3) ORG27569 packs against TMH6, sterically hindering movements of this helix that have been shown to be important for receptor activation.

Over the past five years the number of internet sites advertising "legal highs" has literally exploded, as have user reports of experiences (both pleasurable and frightening) with these substances and the number of emergency room visits by users. Although the majority of these "legal highs" have been described as bath salts and herbal extracts, most contain neither plant derived compounds nor components of personal hygiene products. So-called "bath salts" largely contain synthetic analogs of the natural compound Khat; spice-related materials, claimed to be "legal marijuana," are mostly synthetic analogs of cannabinoid receptor ligands that were developed as research tools. This review describes the emergence and properties of these two groups of "legal highs" from a medicinal chemist's perspective.

An iterative method of estimating permittivity and window thickness with high precision is developed for half wavelength resonant waveguide windows for use in a lower hybrid launcher for DIII-D. The high Q factor of half-wavelength windows results in extreme sensitivity of return loss on small deviations in permittivity. Permittivity and loss tangent measurements of Morgan AL-995 99.5% aluminum oxide ceramic using a waveguide resonant cavity per ASTM D2520-13 determine variation of permittivity with frequency. Measurement of window resonant frequency in conjunction with the slope of permittivity from waveguide cavity measurements determine required thickness of a resonant window within 5 MHz of the desired resonant frequency. Methods to improve measurement accuracy of resonant peaks on a vector network analyzer are discussed. A sensitivity study to dimensional variations in window or sample rod geometry, and shift in resonant frequency due to RF heating of the window material is conducted.

GPR55 is a class A G protein-coupled receptor (GPCR) that has been implicated in inflammatory pain, neuropathic pain, metabolic disorder, bone development, and cancer. Initially deorphanized as a cannabinoid receptor, GPR55 has been shown to be activated by non-cannabinoid ligands such as l-α-lysophosphatidylinositol (LPI). While there is a growing body of evidence of physiological and pathophysiological roles for GPR55, the paucity of specific antagonists has limited its study. In collaboration with the Molecular Libraries Probe Production Centers Network initiative, we identified a series of GPR55 antagonists using a β-arrestin, high-throughput, high-content screen of ~300000 compounds. This screen yielded novel, GPR55 antagonist chemotypes with IC50 values in the range of 0.16-2.72 μM [Heynen-Genel, S., et al. (2010) Screening for Selective Ligands for GPR55: Antagonists (ML191, ML192, ML193) (Bookshelf ID NBK66153; PMID entry 22091481)]. Importantly, many of the GPR55 antagonists were completely selective, with no agonism or antagonism against GPR35, CB1, or CB2 up to 20 μM. Using a model of the GPR55 inactive state, we studied the binding of an antagonist series that emerged from this screen. These studies suggest that GPR55 antagonists possess a head region that occupies a horizontal binding pocket extending into the extracellular loop region, a central ligand portion that fits vertically in the receptor binding pocket and terminates with a pendant aromatic or heterocyclic ring that juts out. Both the region that extends extracellularly and the pendant ring are features associated with antagonism. Taken together, our results provide a set of design rules for the development of second-generation GPR55 selective antagonists.

Despite the therapeutic promise of the subnanomolar affinity cannabinoid CB2 antagonist, 5-(4-chloro-3-methylphenyl)-1-[(4-methylphenyl)methyl]-N-[(1S,2S,4R)-1,3,3-trimethylbicyclo[2.2.1]hept-2-yl]...

A high power resonant three phase switch mode power supply has been constructed at University of Wisconsin to drive a klystron tube. Utilization of a resonant transformer with loosely coupled secondaries allows generation of high boost ratios exceeding the turns ratio while providing high efficiency. Use of nanocrystalline iron cores provides high volt seconds while maintaining low loss at high switching frequencies. Analytic models are developed and compared to measured data from two different size resonant transformers and effects of turns ratio, load resistance, and primary are examined and compared to theory.

Alleviation of neuropathic pain by cannabinoids is limited by their central nervous system (CNS) side effects. Indole and indene compounds were engineered for high hCB1R affinity, peripheral selectivity, metabolic stability, and in vivo efficacy. An epithelial cell line assay identified candidates with

Cannabinoid receptor 1 (CB1) antagonists are potentially useful for the treatment of several diseases. However, clinical development of several CB1 antagonists was halted due to central nervous system (CNS)-related side effects including depression and suicidal ideation in some users. Recently, studies have indicated that selective regulation of CB1 receptors in the periphery is a viable strategy for treating several important disorders. Past efforts to develop peripherally selective antagonists of CB1 have largely targeted rimonabant, an inverse agonist of CB1. Reported here are our efforts toward developing a peripherally selective CB1 antagonist based on the otenabant scaffold. Even though otenabant penetrates the CNS, it is unique among CB1 antagonists that have been clinically tested because it has properties that are normally associated with peripherally selective compounds. Our efforts have resulted in an orally absorbed compound that is a potent and selective CB1 antagonist with limited penetration into the CNS.

There are numerous medicinal chemistry reports in the literature describing the pharmacological properties of thousands of narcotics, stimulants, hallucinogens, sedative-hypnotic drugs, cannabinoids, and other psychoactive substances as well as synthetic methods for their preparations. This information, while essential for the advancement of science, has been used by clandestine chemists to manufacture and market an endless variety of analogs of so-called designer drugs. In this review, we describe how clandestine chemists used the principles of medicinal chemistry to design molecules, referred to as designer drugs, that elicit the effects of opioids, amphetamine and analogs, cannabinoids, and phencyclidine analogs while circumventing the law.

Deuterium-labeled analogs of the topoisomerase inhibitor batracylin were prepared for metabolism studies to further its evaluation as an antitumor agent. Established syntheses of unlabeled batracylin were adapted for the preparation of deuterated batracylin that was trideuterated in the quinazoline ring (d3-batracylin 5), tetradeuterated in the isoindolo ring (d4-batracylin 11), and heptadeuterated in both rings (d7-batracylin 12). Extensive exchange of deuterium or hydrogen in the quinazoline ring was observed from an intermediate in the final concentrated sulfuric acid promoted deblocking/cyclodehydration step of the synthesis. Introduction of deuterated concentrated sulfuric acid in the final step both retained the label in the quinazoline-labeled product and enabled extended labeling of a more exhaustively deuterated analog. Batracylin itself did not readily exchange aromatic protons under the reaction conditions but did loose and scramble deuterium atoms during mass spectral analysis leading to an under calculation of the deuterium content in the quinazoline ring. These results identify a chemical exchange process that can either undo, maintain, or facilitate the labeling process and also mass spectral analyses issues that must be taken into account to characterize and utilize these analogs and, more broadly, that can be recognized as potentially applicable to other classes of compounds. Copyright © 2010 John Wiley & Sons, Ltd.

Salvinorin A, the primary psychoactive derivative of the hallucinogenic herb Salvia divinorum, is a potent and highly selective kappa-opioid receptor (KOR) agonist. Several recent studies, however, have suggested endocannabinoid system mediation of some of its effects.This study represents a systematic examination of this hypothesis.Salvinorin A was isolated from S. divinorum and was evaluated in a battery of in vitro and in vivo procedures designed to detect cannabinoid activity, including CB(1) receptor radioligand and [(35)S]GTPgammaS binding, calcium flux assay, in vivo cannabinoid screening tests, and drug discrimination.Salvinorin A did not bind to nor activate CB(1) receptors. In vivo salvinorin A produced pronounced hypolocomotion and antinociception (and to a lesser extent, hypothermia). These effects were blocked by the selective KOR antagonist, JDTic, but not by the CB(1) receptor antagonist rimonabant. Interestingly, however, rimonabant attenuated KOR activation stimulated by U69,593 in a [(35)S]GTPgammaS assay. Salvinorin A did not substitute for Delta(9)-tetrahydrocannabinol (THC) in mice trained to discriminate THC.These findings suggest that similarities in the pharmacological effects of salvinorin A and those of cannabinoids are mediated by its activation of KOR rather than by any direct action of salvinorin A on the endocannabinoid system. Further, the results suggest that rimonabant reversal of salvinorin A effects in previous studies may be explained in part by rimonabant attenuation of KOR activation.

Antagonists or inverse agonists of the cannabinoid CB1 receptor (CB1R) reported from the 2006–2007 period are reviewed. The compounds are either variations of the archetypical cannabinoid CB1 inverse agonist rimonabant (SR141716) or are other structures less obviously related to the archetype. Many of the former class replace the core pyrazole ring of rimonabant with other ring systems to display/arrange the appended binding/activity elements. A structure-activity relationship evolves from bioassays of these compounds that also provides a more detailed understanding of the molecular mechanism of the binding to and stabilization of the active and inactive states of the constitutively active CB1R. In addition to diverse variations of the core ring and appended substituents, conformationally constrained analogs with high affinity were revealed, a number of which do not fit a one-to-one atom correspondence with the putatively active conformations of the rimonabant template and other active analogs. Diphenylmethyl analogs were a repeated motif in structures where core rings were either absent or played less restrictive roles in structures pursuing higher conformational freedom. Bicyclic nitrogen heterocyclic ring systems as the central core structures were reported, as were linear structures including phenyl ureas and taranabant analogs. Finally, peptides in the hemopressin class were presented as CB1 antagonists. Drug Dev Res 70:601–615, 2009. © 2009 Wiley-Liss, Inc.

Type 1 cannabinoid receptor (CB1) antagonists might be useful for treating obesity, liver disease, metabolic syndrome, and dyslipidemias. Unfortunately, inhibition of CB1 in the central nervous system (CNS) produces adverse effects, including depression, anxiety and suicidal ideation in some patients, which led to withdrawal of the pyrazole inverse agonist rimonabant (SR141716A) from European markets. Efforts are underway to produce peripherally selective CB1 antagonists to circumvent CNS-associated adverse effects. In this study, novel analogues of rimonabant (1) were explored in which the 1-aminopiperidine group was switched to a 4-aminopiperidine, attached at the 4-amino position (5). The piperidine nitrogen was functionalized with carbamates, amides, and sulfonamides, providing compounds that are potent inverse agonists of hCB1 with good selectivity for hCB1 over hCB2. Select compounds were further studied using in vitro models of brain penetration, oral absorption and metabolic stability. Several compounds were identified with predicted minimal brain penetration and good metabolic stability. In vivo pharmacokinetic testing revealed that inverse agonist 8c is orally bioavailable and has vastly reduced brain penetration compared to rimonabant.

The cannabinoid receptor antagonist SR144528 was synthesized by an approach that enabled the incorporation of high specific activity tritium label while circumventing the lability of the target compound to catalytic hydrogenation. Lithium aluminum tritide of less than maximum specific activity was employed to introduce tritium, resulting in an H/T incorporation indicative of no kinetic isotope effect for the hydride/tritide reduction of a methyl benzoate. Copyright © 2005 John Wiley & Sons, Ltd.

The development of an easy and inexpensive immunoassay to measure the limited quantities of endogenous cannabinoids found in the body would be beneficial for both cannabinoid researchers and clinicians. This report describes the hapten design and carrier molecule strategy that we used to generate a panel of monoclonal antibodies (mAB) to the endogenous cannabinoid anandamide (N-arachidonylethanolamide, AEA). We designed and successfully prepared a hapten, N-arachidonyl-7-amino-6-hydroxy-heptanoic acid (AHA), which retained the basic characteristic features of anandamide--the carboxamide, the hydroxyl and the lipophilic arachidonyl moiety with its skipped double bond system, while still allowing attachment to protein. In addition, a secondary alcohol structure was added to reduce the potential for biological hydrolysis of the hapten. Because of the diverse responses obtained after coupling this hapten to four different carriers, we determined that the type of carrier molecule used was particularly important for generating anti-anandamide antibodies. Described in this report are the characteristics of a panel of 11 mAB, generated from four separate fusions, with a range of relative affinities and cross reactivities. Excellent selectivity for anandamide vs. two other endogenous cannabinoids and arachidonic acid was achieved this strategy (cross-reactivities5%). In addition, at least one mAB maintained specificity for anandamide compared to two very closely related fatty acid amide molecules. However, the IC50 values in a standard enzyme-linked immunosorbent assay (ELISA) format (ca. 2-3 microM) indicate that improvement in antibody affinities or assay format will be required for an immunoassay to measure endogenous levels. Such work is underway.

Upon irradiation with a 450 W high-pressure mercury lamp, the CB1 cannabinoid antagonist N-(piperidinyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR14-1716; 1) undergoes a photocyclization reaction to yield a single reaction product. This product, 2, the structure of which is based on a pyrazolo[1,5-f]phenanthridine ring system, was established by two-dimensional NMR techniques (COSY, HSQC, HMBC and ROESY), and was later confirmed by single-crystal x-ray diffraction analysis. The crystal structure shows two independent molecules of 3 and a half molecule of the 1,2-dichloroethane solvate. Compound 2 has reasonably high affinity for the CB1 receptor (Ki = 48.0 ± 2.7 nM). Copyright © 2003 John Wiley & Sons, Ltd.

A mild method for the cleavage of an acetal to afford a rearrangement sensitive diol using B-chlorocatecholborane was developed for the synthesis of the endogenous cannabinoid neurochemical messenger 2-arachidonoylglycerol. The tendency for rearrangement of 2-arachidonoylglycerol to the corresponding 1-arachidonoylglycerol was precluded with this reagent. Features of the partial recyclization to an isomeric acetal provide mechanistic detail.

Analogues of the biaryl pyrazole N-(piperidinyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716; 5) were synthesized to investigate the structure−activity relationship (SAR) of the aminopiperidine region. The structural modifications include the substitution of alkyl hydrazines, amines, and hydroxyalkylamines of varying lengths for the aminopiperidinyl moiety. Proximity and steric requirements at the aminopiperidine region were probed by the synthesis of analogues that substitute alkyl hydrazines of increasing chain length and branching. The corresponding amide analogues were compared to the hydrazides to determine the effect of the second nitrogen on receptor binding affinity. The N-cyclohexyl amide 14 represents a direct methine for nitrogen substitution for 5, reducing the potential for heteroatom interaction, while the morpholino analogue 15 adds the potential for an additional heteroatom interaction. The series of hydroxyalkyl amides of increasing chain length ...

The central cannabinoid receptor antagonist SR141716, N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide, was synthesized from commercially available starting materials. Condensation of an aryl hydrazine with a diketone followed by base promoted isomerization/cyclization of the intermediate anti-imine gave the pyrazole acid which was converted to the title hydrazide via its acid chloride. Facile iodination via metallation followed by in situ trapping with an iodine source gave a modest yield of the iodinated SR141716. The iodine was selectively reduced with tritium gas and catalyst while retaining the three aryl chlorine atoms in the structure. The tritiated SR141716 exhibited a tritium-proton nOe both definitively identifying the position of the tritium as well as the sought isomer of the diarylpyrazole. This work provides a direct method for the preparation of preferred iodinated aryl substrates that offer advantages where selectivity and high incorporation in catalytic reduction is sought. Copyright © 2002 John Wiley & Sons, Ltd.

Auxiliary heating and current drive using RF waves such as the electron Bernstein wave (EBW) promises to advance the performance of the reversed field pinch (RFP). In previous computational work [1], a hypothetical edge-localized current drive is shown to suppress the tearing activity which governs the macroscopic transport properties of the RFP. The ideal conditions for tearing stabilization include a reduced toroidal induction, and precise width and radial position of the Gaussian-shaped external current drive. In support of the EBW experiment on the Madison Symmetric Torus, an integrated modeling scheme now incorporates ray tracing and Fokker-Plank predictions of auxiliary current into single fluid MHD. Simulations at low Lundquist number (S ∼ 104) generally agree with the previous work; significantly more burdensome simulations at MST-like Lundquist number (S ∼ 3×106) show unexpected results. The effect on nonlinearly saturated current profile by a particular RF-driven external force decreases in magn...

2-Arachidonylglycerol (2-Ara-Gl) was synthesized via the intermediacy of its 1,3-phenylboronic acid ester. The boronate ester is easily stable enough to enable chromatographic resolution from the corresponding 1-Ara-Gl boronate ester on normal phase elution yet immediately and completely hydrolyzes to 2-Ara-Gl and phenylboronic acid, without isomerization, by simple solution in aqueous-organic solvents. The phenylboronate ester of this 2-acylglycerol has the added advantage of being markedly more stable to both isomerization and oxidation upon storage than the labile 2-Ara-Gl.

(-)-Hexahydrocannabinol 7 was synthesized enantioselectively under mild conditions through the ortho quinone methide mediated cyclization of the adduct of R-(+)-citronellal and the bisethoxyethyl ether of olivetol. The conditions enabled the ene product, 1, 2-dihydrocannabidiol 6, to be isolated as well.

An overview of recent results from the MST reversed field pinch programme is presented. With neutral beam injection, bursty energetic particle (EP) modes are observed. The profiles of the magnetic and density fluctuations associated with these EP modes are measured using a far infrared interferometer-polarimeter. Equilibrium reconstructions of the quasi-single-helicity 3D helical state are provided by the V3FIT code that now incorporates several of MST's advanced diagnostics. The orientation of the helical structure is controlled using a new resonant magnetic perturbation technique. Gyrokinetic simulations based on experimental equilibria predict unstable trapped-electron modes (TEMs), and small-scale density fluctuations are detected in improved-confinement plasmas with TEM-like features. Upgraded pellet injection permits study of density and beta limits over MST's full range of operation, and an MST-record line-average density of 0.9 ×1020 m3 (n/nG = 1.4) has been obtained. Impurity ion temperature measurements reveal a charge-to-mass-ratio dependence in the rapid heating that occurs during a sawtooth crash. Runaway of NBI-born fast ions during the impulsive sawtooth event agrees with test-particle theory. Magnetic self-organization studies include measurements of the dynamo emf with an applied ac inductive electric field using oscillating field current drive.

Tritiated morphine of high specific activity was protected at the 3-position by acetylation and subjected to glucuronidation by Koenigs-Knorr procedure with methyl 2,3,4-tri-0-acetyl-1-bromo-1-deoxy-D-glucopyranuronate and silver carbonate. Fully protected morphine-6-glucuronide was obtained in 42% yield and 95% radiochemical purity as determined by TLC-RAM. Alkali catalyzed solvolysis in two steps furnished [1-3H]morphine-6-β-D-glucuronide in 23% overall radiochemical yield and 99% radio-chemical purity determined by HPLC-liquid scintillation counting and TLC-RAM. Copyright © 1999 John Wiley & Sons, Ltd.

A WIN 35,065-2 analog, 3β-(4-iodophenyl)tropane-2β-pyrrolidine carboxamide (RTI-229), has been radiolabelled with iodine-125 by radioiododestannylation of the corresponding trimethyltin derivative using carrier-free sodium iodide-125 as the isotope source. Purification by reversed-phase HPLC gives [125I]RTI-229 in good yield (89·4%) with high radiochemical purity (>99%) and high specific activity (2125 mCi/μmol, 78·6 GBq/μmol, based on the specific activity of the Na125I used). Copyright © 1999 John Wiley & Sons, Ltd.