Nagaoka ferromagnetism observed in a quantum dot plaquette.

Engineered, highly controllable quantum systems are promising simulators of emergent physics beyond the simulation capabilities of classical computers1. An important problem in many-body physics is itinerant magnetism, which originates purely from long-range interactions of free electrons and whose existence in real systems has been debated for decades2,3. Here we use a quantum simulator consisting of a four-electron-site square plaquette of quantum dots4 to demonstrate Nagaoka ferromagnetism5. This form of itinerant magnetism has been rigorously studied theoretically6-9 but has remained unattainable in experiments. We load the plaquette with three electrons and demonstrate the predicted emergence of spontaneous ferromagnetic correlations through pairwise measurements of spin. We find that the ferromagnetic ground state is remarkably robust to engineered disorder in the on-site potentials and we can induce a transition to the low-spin state by changing the plaquette topology to an open chain. This demonstration of Nagaoka ferromagnetism highlights that quantum simulators can be used to study physical phenomena that have not yet been observed in any experimental system. The work also constitutes an important step towards large-scale quantum dot simulators of correlated electron systems.

The sigma enigma: in vitro/in silico site-directed mutagenesis studies unveil σ1 receptor ligand binding.

The σ1 receptor is an integral membrane protein that shares no homology with other receptor systems, has no unequivocally identified natural ligands, but appears to play critical roles in a wide variety of cell functions. While the number of reports of the possible functions of the σ1 receptor is increasing, almost no information about the three-dimensional structure of the receptor and/or possible modes of interaction of the σ1 protein with its ligands have been described. Here we performed an in vitro/in silico investigation to analyze the molecular interactions of the σ1 receptor with its prototypical agonist (+)-pentazocine. Accordingly, 23 mutant σ1 isoforms were generated, and their interactions with (+)-pentazocine were determined experimentally. All direct and/or indirect effects exerted by the mutant residues on the receptor-agonist interactions were reproduced and rationalized in silico, thus shining new light on the three-dimensional structure of the σ1 receptor and its ligand binding site.

Cytotoxic activities of hydroxyethyl piperazine-based σ receptor ligands on cancer cells alone and in combination with melphalan, PB28 and haloperidol.

σ Receptor ligands are attracting interest as possible anti-cancer agents because of their ability to induce cell death by different mechanisms. In this study we investigated the cytotoxic effects of 12 recently developed σ-receptor ligands in a panel of eight different human tumor cell lines by either the crystal violet or MTT assays. The results show that σ ligands have broad cytotoxic activity on a number of human cancer cell lines with IC50 values in the low µM range. In addition, apoptosis was observed by the annexin-V/PI double staining method when RPMI 8226 human multiple myeloma cells were treated with a representative σ ligand, (R)-2b. Combination of (R)-2b with melphalan led to a higher apoptotic rate than with the drug alone. Likewise, combined treatment of (R)-2b with the known high affinity σ2-agonist PB28 showed an additive effect on the induction of apoptosis in the RPMI 8226 line. In contrast, combinations of (R)-2b with the known σ1-antagonist haloperidol lead to a significant reduction in the cytotoxic activity of (R)-2b. These results support the idea that (R)-2b acts as a σ-agonist to cause the death of RPMI 8226 cells.

Few-body bound states in dipolar gases and their detection.

We consider dipolar interactions between heteronuclear molecules in a low-dimensional setup consisting of two one-dimensional tubes. We demonstrate that attraction between molecules in different tubes can overcome intratube repulsion and complexes with several molecules in the same tube are stable. In situ detection schemes of the few-body complexes are proposed. We discuss extensions to many tubes and layers, and outline the implications on many-body physics.

π phases in balanced fermionic superfluids on spin-dependent optical lattices.

We study a balanced two-component system of ultracold fermions in one dimension with attractive interactions and subject to a spin-dependent optical lattice potential of opposite sign for the two components. We find states with different types of modulated pairing order parameters which are conceptually similar to π phases discussed for superconductor-ferromagnet heterostructures. Increasing the lattice depth induces sharp transitions between states of different parity. While the origin of the order parameter oscillations is similar to the Fulde-Ferrel-Larkin-Ovchinnikov phase for paired states with spin imbalance, the current system is intrinsically stable to phase separation. We discuss experimental requirements for creating and probing these novel phases.

Methylated analogues of methyl (R)-4-(3,4-dichlorophenylacetyl)- 3-(pyrrolidin-1-ylmethyl)piperazine-1-carboxylate (GR-89,696) as highly potent kappa-receptor agonists: stereoselective synthesis, opioid-receptor affinity, receptor selectivity, and functional studies.

Analogues of the kappa-receptor agonist methyl (R)-4-(3,4-dichlorophenylacetyl)-3-(pyrrolidin-1-ylmethyl)piperazine-1-carboxylate (GR-89,696, 6) bearing an additional methyl substituent in the side chain are synthesized and evaluated for their kappa-receptor affinity and selectivity. A key step in the synthesis is the stereoselective reductive amination of the ketones 9, 18, and 19 with pyrrolidine and NaBH(3)CN, which succeeds only in the presence of the Lewis acid Ti(OiPr)(4). Whereas the BOC-substituted ketone 9 affords the unlike and like diastereomers of 10 in a ratio of 70:30, the diastereoselectivity during the reductive amination of the butyl and phenyl substituted ketones 18 and 19 is enhanced to 85:15 (butyl derivative) and >95:<5 (phenyl derivative) in favor of the unlike diastereomers. In receptor binding studies using the radioligand [(3)H]U-69,593 the (S,S)-configured methyl carbamate (S,S)-14 reveals the highest kappa-receptor affinity (K(i) = 0.31 nM) within this series, even exceeding the lead kappa-agonist 6 (GR-89,696). A slightly reduced kappa-receptor affinity is observed with the propionamide (S,S)-13 (K(i) = 0.67 nM). The kappa-receptor affinity of piperazines with acyl or alkoxycarbonyl residues at both nitrogen atoms (11, 13, 14) decreases in the order (S,S) > (R,R) > (S,R) > (R,S). The methyl carbamate (S,S)-14 discloses a unique activity profile also binding at mu-receptors in the subnanomolar range (K(i) = 0.36 nM). In a functional assay, i.e., by measuring acetylcholine release in rabbit hippocampus slices, the agonistic effects of the methyl carbamate (S,S)-14 and the propionamide (S,S)-13 are demonstrated. Only weak kappa- and mu-receptor affinities are found with the butyl- and phenyl-substituted piperazines 22 and 23. However, considerable sigma(1)-receptor affinity is determined for the enantiomeric, unlike-configured butyl derivatives (R,S)-22 and (S,R)-22 with K(i)-values of 40.2 nM and 81.0 nM, respectively.

Synthesis and stereoselective kappa-receptor binding of methylated analogues of GR-89.696.

Stereoselective synthesis of all four stereoisomers of methylated analogues 8 of the kappa-receptor agonist GR-89.696 is presented. Starting with orthogonally protected piperazine derivatives (R,R)-4 and (S,S)-4, the reaction sequence involves oxidation, reductive amination and modification of the piperazine nitrogen protective groups. The configuration of the stereocentre in alpha-position to the pyrrolidine moiety is determined by X-ray structure analysis of (R,S)-8. In receptor-binding studies with the radioligand U-69.593, the stereoisomer with (S)-configuration at both stereogenic centres (S,S)-8 displayed the highest kappa-receptor affinity with a K(i)-value of 0.67 nM.

Stereoselective syntheses and CNS activity of novel tricyclic amines.

The enantiomerically pure amines (+)-5, (-)-9, (+)-11 and (+)-12 are stereoselectively prepared by reductive amination of the ketone (-)-4 [-->(+)-5], LiAlH4 reduction of the oxime (-)-7 followed by reductive methylation [-->(-)-9], SN2-substitution of the benzenesulfonate 10 [-->(+)-11] and reductive methylation of (+)-11 [-->(+)-12]. In the same way the racemic amines (+/-)-5, (+/-)-9, (+/-)-11 and (+/-)-12 are accessible starting from the racemic ketone (+/-)-4. Kinetic resolution of the racemic ketone (+/-)-4 with baker's yeast leads to the dextrorotatory ketone (+)-4 (86% ec), which is transformed via the methanesulfonate 16 into the tricyclic amines (-)-11 and (+)-17. Weak sedative effects are observed after application of the amines (+)-5, (+/-)-5, 0-9, (+/-)-9(+)-12, and (+/-)-12 to mice. Strong sedation is caused by (+/-)-11 with the dextrorotatory enantiomer (+/-)-11 being more effective than the levorotatory enantiomer (-)-11.

Molecular imaging of σ1 receptors in vivo: current status and perspectives.

It is widely accepted that sigma (σ) receptors represent a new and different avenue in the possible pharmacological treatment of cancer and several brain-related disorders. Of the two different σ receptor types the σ1 receptors are assumed to be of major impact for brain diseases. Molecular imaging of brain σ1 receptors with positron emission tomography (PET) or single photon emission computed tomography (SPECT) may provide a significant contribution to the understanding of the cross-talk between σ1 receptors and inter- and intracellular signalling systems. New insights into these functional interrelationships will allow a better diagnosis of brain and cancerous diseases and direct a rational development of new therapeutic concepts.

Interactions and magnetism in graphene boundary states.

We analyze interaction effects on boundary states of single layer graphene. Near a half filled band, both short- and long-ranged interactions lead to a fully spin-polarized configuration. In addition, the band of boundary states acquires a finite dispersion as a function of the momentum parallel to the edge, induced by the interactions. Away from half filling the wave function develops charge correlations similar to those in a Wigner crystal, and the spin strongly alternates with the occupation of the boundary states. For certain fillings the ground state has a finite linear momentum, leading to the formation of persistent currents.

[CNS-active substances: synthesis of epoxybenzoxocines]. / ZNS-Wirkstoffe: Synthese von Epoxybenzoxocinen.

The 2-(2-Bromophenyl)-acetaldehyde acetals 8 are treated with n-BuLi and the aldehydes 7 and 11 to form the hydroxyacetales 9 and 12, respectively. 9 is cyclized under acidic conditions to the epoxybenzoxocine 2; analogously 12 yields the epoxydibenzoxocine 14.

[Synthesis and central effects of 4-hydroxy-(alkyl)- and 4-amino-(alkyl)-substituted 2,6-epoxy-3-benzoxocines]. / Synthese und zentrale Wirkungen von 4-hydroxy-(alkyl)- und 4-amino-(alkyl)-substituierten 2,6-epoxy-3-benzoxocinen.

The tricyclic hemiacetal 1 is transformed with amines to the N/O-acetals 3 and 10, with nitromethane to the 4-nitromethyl derivative 13, and with the Wittig reagents 15a and 15b to the 2-benzopyrans 16 and 19. Reduction and methylation of 13 yield the tertiary amine 4; through three steps the secondary amine 18 and the tertiary amine 5 are prepared from 16 and 19, respectively. The 1,3-dioxane ring of all these 2,6-epoxy-3-benzoxocine derivatives exists in the chair conformation with an equatorial C-4 substituent. After application of the amines 5, 11c, and 18 mice do not show any symptoms of central activity; weak CNS-effects are observed with the alcohols 1 and 2. For the tertiary amine 4, which causes considerable central effects (Straubtail-phenomenon, convulsions, etc.), an ED50 of 78 mg/kg is determined in the mouse "writhing"-test.

[Benzomorphan analogs with doxpicomine partial structure: synthesis andpsychopharmacologic investigations of 5-aminomethyl- and 5-(alpha-aminobenzyl)- substituted 2,6-epoxy-3-benzoxocines]. / Benzomorphan-Analoga mit Doxpicomin Partialstruktur: Synthese und psychopharmakologische Untersuchung von 5-Aminomethyl und 5-(alpha-Aminobenzyl) substituierten 2,6-Epoxy-3-benzoxocinen.

Addition of the beta-alanine derivative 6 to the homophthalaldehyde monoacetal 5 and subsequent LiAlH4-reduction led to the dihydroxy acetal 8, which was cyclized with acid to give the 5-aminomethyl-2,6-epoxy-3-benzoxocines 2a and 2b. The reaction of 5 with the anion of the beta-lactam 9 yielded two separable diastereomers: 10a with u,l-configuration and 10b with 1,1-configuration. Via the 2-benzopyran 11a (11b), the aminoalcohol 12a (12b), and the secondary amine 13a (13b), the beta-lactam adduct 10a (10b) was transformed to give the 5-(alpha-dimethylaminobenzyl)-2,6-epoxy-3-benzoxocine 3d (3b). The relative configurations of all these "beta-lactam route" products (10-13, 3d, and 3b) were established by their 1H-NMR-spectra. Attempts failed to get the missing diastereomers 3a and 3c by epimerization of the beta-lactams 11a and 11b or by reductive amination of the benzoyl derivatives 17a and 17b. Finally, 3a and 3c were obtained by phenylmagnesium bromide addition to the nitriles 21a and 21b, followed by LiAlH4-reduction, formaldehyde/NaBH3CN methylation and chromatographic separation. In the Irwin-screen (mouse) only 2a.HCl, 3b, and 3d (100 mg/kg body weight) caused weak central effects.

[5,6-Dihydro-6-methoxy-2H-pyran-3(4H)-one, a building block for the synthesis of CNS agents]. / 5,6-Dihydro-6-methoxy-2H-pyran-3(4H)-on, Baustein zur Synthese von ZNS-Wirkstoffen.

The phenyl-pyranyl-piperidin derivative 5, prepared from the title compound 2, shows a strong stimulating effect in animals. Reactions of 2 with 2-amino-phenylcarbonyl derivatives or phenylhydrazine can lead to [3,2-b] as well as [3,4-b] annulated pyranes. Regioselective reactions in 2- or 4-position of 2 are successful after conversion to the enamine 14a, the silylenolether 24 and the lithioenamine 29. Cycloadditions, cyclocondensations or electrophilic aldoleractions yield the pyrano-pyranes 16 and 19a, resp., or the hydroxybenzyl- and hydroxybenzylidenpyranes 25 and 30, resp.

Trends in health care financing: opportunities for family planning agencies.

PIP: In response to spiraling health care costs in the US, several alternative health care delivery systems have evolved. The delivery of subsidized family planning services in particular is being affected by declining levels of government support. The most rapidly growing of alternative delivery systems is the health maintenance organization (HMO). HMOs provide a voluntarily enrolled population a guaranteed, specific range of physician and hospital services in return for a fixed periodic payment. There are 3 types of HMO: the group model, in which doctors are members of a partnership or service corporation that contracts with employers or individuals to provide medical services; the taff model, in which physicians are direct employees of the HMO; and the independent practice association (IPA) model, a physicians' group that enters into a contract with an HMO and receives reimbursement for every patient seen. In 1986, over 21 million Americans were enrolled in approximately 262 HMOs around the country. HMOs are unequaled in their success at reducing hospital utilization; they have achieved savings of hospital costs of 20-40%. Another system for delivering and financing health care is the preferred provider organization (PPO) under which patients are assigned to a designated panel of health care providers who offer services according to a discounted fee schedule. New hybrid systems that combine many of the features of both systems are emerging. Most of the newly organized health care delivery systems described focus on utilization control and keeping costs down. A common way of ensuring coordinated health care delivery is through primary care case management. To initiate or establish relationships with HMOs or other health care delivery systems, family planning agencies should consider such activities as: undertaking surveys to study the market; training new employees on developments in health care financing; and recruiting board members with HMO experience.^ieng

[Synthesis of homochiral 5,9-epoxybenzocyclooctenes with amino substitutents: relationship between structure and CNS activity]. / Synthese homochiraler 5,9-Epoxybenzocyclooctene mit Aminsubstituenten: Zusammenhang zwischen Struktur und ZNS-Aktivität.

This paper deals with the synthesis and psychopharmacological effects of variations of the sedative and analgesic tricyclic amines 3a and 3b: Starting with the homochiral ketone 4 the amines 5 (primary amino group in equatorial position), 7 (axially oriented dimethylamino group), 9 (additional phenyl residue in position 7), 13b, and 14b (equatorially and axially arranged dimethylaminomethyl group) and 23 and 24 (axial amino group shifted to position 9) are prepared. BBr3 cleaves the phenolic ethers of the secondary amine (+/-)-3a to yield the aminodiphenol (+/-)-10. -Keeping mice under observation for behavioral anomalies (Irwin screen) and analgesic activity (writhing test) shows, that the amines 5, 7, 9, (+/-)-10, 13b, 14b, and 23 do not reach the sedative and analgesic effects of the amines 3a and 3b, described by us.

[Synthesis and CNS-activity of spirocyclic pethidine and prodine analogs]. / Synthese und ZNS-Aktivität spirocyclischer Pethidin- und Prodin-Analoga.

The bromoacetals 5a and 5b react with n-butyllithium and the piperidone 7 to yield the hydroxyacetals 8b and 8c, respectively. Cyclization of 8b and 8c followed by acid hydrolysis affords the spirocyclic hemiacetals 10b and 10c which are oxidized by PCC to give the spirocyclic prodine analogues 4b and 4c. The corresponding spirocyclic pethidine derivative 2 is prepared by alkylation of the 2-benzopyran-3-one 16 with N-Lost (17). In the mouse writhing test the spiropethidine 2 is not analgesic active up to a dose of 20 mg/kg body weight (bw). In the spirocyclic prodine series the methylated lactone 4c is the most active analgesic with an ED50-value (ED50 = 9.2 mg/kg bw) in the range of the ED50-value of tramadol.

[Synthesis and CNS- activity of cis-pyrano[2,3-b]-[1,4]dioxane derivatives ]. / Synthese und ZNS-Wirkungen von cis-Pyrano[2,3-b]-[1,4]-dioxanderivaten.

The alcohols 2, the amines 5, 7 and 10, the indole- and quinoline-derivatives 13 and 14, the enamines 3 and 4 and the silylenolethers 17 and 18 were prepared starting with the title compound 1. The 1-(7-phenyl-7-pyranodioxinyl)-piperidines 10-cis and 10-trans show striking CNS-activity. The transisomer is about twice as active as the cis-isomer.

[Synthesis of enantiomerically pure 6,10-epoxybenzocycloocten-7-amines with CNS activity]. / Synthese enantiomerenreiner 6,10-Epoxybenzocycloocten-7-amine mit ZNS-Aktivität.

In an oxa-Pictet-Spengler reaction the methyl (S)-phenyllactate 6 and methyl levulinate (7a) are condensed to the 2-benzopyrans cis-8a and trans-8a, which react with CH3I to yield the dimethyl ethers cis-9a and trans-9a. Cis-9a and trans-9a can be separated by medium pressure liquid chromatography. In the subsequent Dieckmann-Cyclisation cis-9a is transformed to the laevorotatory beta-ketoester (-)-10a, while the dextrorotatory enantiomer (+)-10a is obtained from trans-9a after C-3-epimerisation. With Eu(hfc)3 the ketone (-)-11, prepared by saponification and decarboxylation of (-)-10a, proves to be enantiomerically pure. By reductive amination, ketone (-)-11 is transformed to the amines (-)-12a and (-)-12b. Symptoms typical for central damping are caused after i.p. application of (-)-12a and (-)-12b to mice. In the mouse writhing-test (-)-12a HCl affords an ED50-value of 7.0 mg/kg, comparable with the ED50-value of tramadol.