Effects of Intra-BLA Administration of PPAR Antagonists on Formalin-Evoked Nociceptive Behaviour,Fear-Conditioned Analgesia,and Conditioned Fear in the Presence or Absence of Nociceptive Tone in Rats

There is evidence for the involvement of peroxisome proliferator-activated receptors (PPARs) in pain, cognition, and anxiety. However, their role in pain–fear interactions is unknown. The amygdala plays a key role in pain, conditioned fear, and fear-conditioned analgesia (FCA). We investigated the effects of intra-basolateral amygdala (BLA) administration of PPARα, PPARβ/δ, and PPARγ antagonists on nociceptive behaviour, FCA, and conditioned fear in the presence or absence of nociceptive tone. Male Sprague-Dawley (SD) rats received footshock (FC) or no footshock (NFC) in a conditioning arena. Twenty-three and a half hours later, rats received an intraplantar injection of formalin or saline and, 15 min later, intra-BLA microinjections of vehicle, PPARα (GW6471) PPARβ/δ (GSK0660), or PPARγ (GW9662) antagonists before arena re-exposure. Pain and fear-related behaviour were assessed, and neurotransmitters/endocannabinoids measured post-mortem. Intra-BLA administration of PPARα or PPARγ antagonists potentiated freezing in the presence of nociceptive tone. Blockade of all PPAR subtypes in the BLA increased freezing and BLA dopamine levels in NFC rats in the absence of nociceptive tone. Administration of intra-BLA PPARα and PPARγ antagonists increased levels of dopamine in the BLA compared with the vehicle-treated counterparts. In conclusion, PPARα and PPARγ in the BLA play a role in the expression or extinction of conditioned fear in the presence or absence of nociceptive tone.     

Zerumbone Ameliorates Neuropathic Pain Symptoms via Cannabinoid and PPAR Receptors Using In Vivo and In Silico Models

Neuropathic pain is a chronic pain condition persisting past the presence of any noxious stimulus or inflammation. Zerumbone, of the Zingiber zerumbet ginger plant, has exhibited anti-allodynic and antihyperalgesic effects in a neuropathic pain animal model, amongst other pharmacological properties. This study was conducted to further elucidate the mechanisms underlying zerumbone’s antineuropathic actions. Research on therapeutic agents involving cannabinoid (CB) and peroxisome proliferator-activated receptors (PPARs) is rising. These receptor systems have shown importance in causing a synergistic effect in suppressing nociceptive processing. Behavioural responses were assessed using the von Frey filament test (mechanical allodynia) and Hargreaves plantar test (thermal hyperalgesia), in chronic constriction injury (CCI) neuropathic pain mice. Antagonists SR141716 (CB₁ receptor), SR144528 (CB₂ receptor), GW6471 (PPARα receptor) and GW9662 (PPARγ receptor) were pre-administered before the zerumbone treatment. Our findings indicated the involvement of CB₁, PPARα and PPARγ in zerumbone’s action against mechanical allodynia, whereas only CB₁ and PPARα were involved against thermal hyperalgesia. Molecular docking studies also suggest that zerumbone has a comparable and favourable binding affinity against the respective agonist on the CB and PPAR receptors studied. This finding will contribute to advance our knowledge on zerumbone and its significance in treating neuropathic pain.     

Synthesis and screening of peptoid arrays on cellulose membranes

Rapid synthesis and screening of compound libraries enables the accelerated identification of novel protein ligands in order to support processes like analysis of protein interactions, drug target discovery or lead structure discovery. SPOT synthesis—a well established method for the rapid preparation of peptide arrays—has recently been extended to the field of nonpeptides. In this contribution we report on the systematic evaluation of the SPOT technique for the assembly of N-alkylglycine (peptoid) library arrays. In the course of this investigation bromoacetic acid 2,4-dinitrophenylester (1a) was identified to be the most suited agent for bromoacetylation in terms of yield and N-selectivity enabling straightforward submonomer synthesis on hydroxy-group rich cellulose membranes. The potential of this method for the rapid identification of novel nonpeptidic protein ligands was demonstrated by synthesis and screening of a library consisting of 8000 peptoids and peptomers (i.e. their hybrids with α-substituted amino acids) allowing the identification of micromolar ligands for the monoclonal antibody Tab-2.     

A Multitarget Approach to Evaluate the Efficacy of Aquilaria sinensis Flower Extract against Metabolic Syndrome

Aquilaria sinensis (Lour.) Spreng is known for its resinous secretion (agarwood), often secreted in defense against injuries. We investigated the effects of A. sinensis flower extract (AF) on peroxisome proliferator-activated receptors alpha and gamma (PPARα and PPARγ), liver X receptor (LXR), glucose uptake, and lipid accumulation (adipogenesis). Activation of PPARα, PPARγ and LXR was determined in hepatic (HepG2) cells by reporter gene assays. Glucose uptake was determined in differentiated muscle (C2C12) cells using 2-NBDG (2-deoxy-2-[(7-nitro-2,1,3-benzoxadiazol-4-yl)amino]-D-glucose). Adipogenesis was determined in adipocytes (3T3-L1 cells) by Oil red O staining. At a concentration of 50 µg/mL, AF caused 12.2-fold activation of PPARα and 5.7-fold activation of PPARγ, while the activation of LXR was only 1.7-fold. AF inhibited (28%) the adipogenic effect induced by rosiglitazone in adipocytes and increased glucose uptake (32.8%) in muscle cells at 50 μg/mL. It was concluded that AF acted as a PPARα/γ dual agonist without the undesired effect of adipogenesis and exhibited the property of enhancing glucose uptake. This is the first report to reveal the PPARα/γ dual agonistic action and glucose uptake enhancing property of AF along with its antiadipogenic effect, indicating its potential in ameliorating the symptoms of metabolic syndrome.     

Cooperativity as quantification and optimization paradigm for nuclear receptor modulators

Nuclear Receptors (NRs) are highly relevant drug targets, for which small molecule modulation goes beyond a simple ligand/receptor interaction. NR–ligands modulate Protein–Protein Interactions (PPIs) with coregulator proteins. Here we bring forward a cooperativity mechanism for small molecule modulation of NR PPIs, using the Peroxisome Proliferator Activated Receptor γ (PPARγ), which describes NR–ligands as allosteric molecular glues. The cooperativity framework uses a thermodynamic model based on three-body binding events, to dissect and quantify reciprocal effects of NR–coregulator binding (K^I_D) and NR–ligand binding (K^II_D), jointly recapitulated in the cooperativity factor (α) for each specific ternary ligand·NR·coregulator complex formation. These fundamental thermodynamic parameters allow for a conceptually new way of thinking about structure–activity-relationships for NR–ligands and can steer NR modulator discovery and optimization via a completely novel approach.

A cooperativity framework describes the formation of nuclear receptor ternary complexes and deconvolutes ligand and cofactor binding into intrinsic affinities and a cooperativity factor, providing a conceptually new understanding of NR modulation.     

Five-coordinate pentafluorobenzothiolate osmium(IV) complexes [Os(SC6F5)4(P(C6H4X-4)3)] (X = OCH3, CH3, F, Cl or CF3): Solid and solution structural characterization

The reactions of OsO₄ with excess of HSC₆F₅ and P(C₆H₄X-4)₃ in ethanol afford the five-coordinate compounds [Os(SC₆F₅)₄(P(C₆H₄X-4)₃)] where X = OCH₃ 1a and 1b, CH₃ 2a and 2b, F 3a and 3b, Cl 4a and 4b or CF₃ 5a and 5b. Single crystal X-ray diffraction studies of 1 to 5 exhibit a common pattern with an osmium center in a trigonal-bipyramidal coordination arrangement. The axial positions are occupied by mutually trans thiolate and phosphane ligands, while the remaining three equatorial positions are occupied by three thiolate ligands. The three pentafluorophenyl rings of the equatorial ligands are directed upwards, away from the axial phosphane ligand in the arrangement “3-up” (isomers a). On the other hand, ³¹P{¹H} and ¹⁹F NMR studies at room temperature reveal the presence of two isomers in solution: The “3-up” isomer (a) with the three C₆F₅-rings of the equatorial ligands directed towards the axial thiolate ligand, and the “2-up, 1-down” isomer (b) with two C₆F₅-rings of the equatorial ligands directed towards the axial thiolate and the C₆F₅-ring of the third equatorial ligand directed towards the axial phosphane. Bidimensional ¹⁹F–¹⁹F NMR studies encompass the two sub-spectra for the isomers a (“3-up”) and b (“2-up, 1-down”). Variable temperature ¹⁹F NMR experiments showed that these isomers are fluxional. Thus, the ¹⁹F NMR sub-spectra for the “2-up, 1-down” isomers (b) at room temperature indicate that the two S-C₆F₅ ligands in the 2-up equatorial positions have restricted rotation about their C–S bonds, but this rotation becomes free as the temperature increases. Room temperature ¹⁹F NMR spectra of 3 and 5 also indicate restricted rotation around the Os–P bonds in the “2-up, 1-down” isomers (b). In addition, as the temperature increases, the ¹⁹F NMR spectra tend to be consistent with an increased rate of the isomeric exchange. Variable temperature ³¹P{¹H} NMR studies also confirm that, as the temperature is increased, the a and b isomeric exchange becomes fast on the NMR time scale.     

Design,synthesis and evaluation of PPAR gamma binding activity of 2-thioxo-4-thiazolidinone derivatives

We designed and synthesized a series of 2-thioxo-4-thiazolidinone derivatives and evaluated them on peroxisome proliferator activated receptor γ(PPARγ) binding activities.Through the biological assays,compounds 18 and 38 were highlighted with K_i values of 12.15 nmol/Land 14.46 nmol/L,respectively.Then structure-activity relationship(SAR) was analyzed to screen privileged structural modifications.Moreover,molecular fitting of these compounds onto the approved drug Rosightazone in the PPARγligand binding domain was performed to elucidate the SAR and explore potential receptor-ligand interactions.These results demonstrate that the 2-thioxo-4-thiazolidinones can be considered as new promising molecular probes with excellent binding activities to PPARγ.     

A tetraruthenium carbonyl cluster bearing indenyl-type ligand as the facial bonding mode

A tetraruthenium carbonyl cluster, (μ₃:η¹:η³:η⁵-3,4,5-trihydroacenaphthylenyl)Ru₄H(CO)₉ (3), was synthesized from (μ₃:η¹:η⁵-dihydroacenaphthylene)Ru₃H₂(CO)₁₂ (2) in chloroform. The molecular structure showed the trihydroacenaphthylenyl ligand to be a rare example of triply bridging nine electron donor ligands, being bound to three ruthenium atoms by the face-capping mode. One ruthenium atom was bonded by the π-cyclopentadienyl coordination mode, whereas the latter two were bound to four carbons in the six-membered ring by the η¹:η³-bonding mode.     

Synthesis and structure of the unsymmetrical β-diimine precursor: The β-iminoamine

The reaction of benzoylacetone with ortho-substituted aniline derivatives gives the unsymmetrical β-iminoamine ligands (5–8) with high yields. A convenient synthesis is described. These compounds have been characterized by NMR and IR spectroscopies. The structure of the β-iminoamine 5, 3-N-(2,6-diisopropylphenylamino)-1-phenyl-1N-(2,6-diisopropylphenylimino)but-2-ene, was solved by X-ray diffraction methods.     

Novel coordination polymers with ferrocene-containing dicarboxylate ligand: Syntheses, crystal structures and properties

A new ferrocene-containing dicarboxylate ligand, L = 5-ferrocene-1,3-benzenedicarboxylic acid, has been prepared. Self-assembly of L, M(II) salts (M = Co and Zn) and chelating ligands dpa or phen (dpa = 2,2′-dipyridylamine and phen = 1,10-phen) gave rise to four new coordination polymers {[Co(L)(dpa)] · 2MeOH}_n (1), {[Zn(L)(dpa)] · 2MeOH}_n (2), {[Co(L)(phen)(H₂O)] · MeOH} (3), [Zn(L)(phen)(H₂O)] · MeOH (4). The isostructural complexes 1 and 2 possess 1D helical chain structures with 2₁ screw axes along the b-direction, and the right- and left-handed helical chains are alternate arrayed into 2D layer structures through hydrogen-bonding interactions; while isostructural complexes 3 and 4 are 1D linear chain structures with phen and ferrocene groups of L as pendants hanging on the different sides of the main chain. A structural comparison of complexes 1–4 demonstrated that the characteristics of subsidiary ligands and slight difference in coordination models of L play very important role in the construction of the complexes. In addition, the redox properties of complexes 1–4, as well as the magnetic properties of complexes 1 and 3 are also investigated.     

Mixed-ligand coordination polymers constructed from flexible 2,2′-biphenyldicarboxylate and rigid isomeric bipyridines

Six coordination polymers have been synthesized and characterized based on dpa and isomeric bipyridine mixed ligands with various metal ions. Complex 1 exhibits a two-dimensional layer structure. Complex 2 is isomorphic to complex 1, with only small differences in bond lengths and bond angles. Complex 3 shows a one-dimensional chain structure composed of interesting pentanuclear Co building units. Complex 4 possesses a two-dimensional (4, 4) layer network, which crystallizes in a homochiral space group. During the synthesis process of complex 4, the dpa ligands decompose and form 2-bpa ligands, which connect with Ni atoms and produce the two-dimensional complex 5. Complex 6 exhibits a three-dimensional supramolecular structural feature constructed from discrete building units with π–π interactions. Furthermore, the magnetic properties of complex 2 are studied.     

Carbonyl rhodium(I) complexes containing (H)PNX (X = O or N) ligands deriving from natural aminoacid–amides. Synthesis, X-ray structure and spectroscopic characterization

The polyfunctional (H)PNX (X = O or N) ligands 1 and 2 react with [Rh(CO)₂Cl]₂ to give the corresponding chloro carbonyl complexes {Rh[κ²-(H)PN](CO)Cl} (1a and 2a), where the neutral ligands coordinate in a κ²-PN bidentate fashion, the square planar coordination being completed by the CO trans to N and the chloride trans to P. In chloroform solution 1a maintains its original structure, while 2a partially transforms into the cationic species {Rh[κ³-(H)PNO](CO)}Cl. The chloroform solutions of 1a and 2a react with AgPF₆ to give the purely cationic species {Rh[κ³-(H)PNO](CO)}PF₆ ([1a]⁺ and [2a]⁺), while addition of Et₃N originates the neutral species {Rh[κ³-PNN′](CO)} (1b and 2b). All the complexes have been characterized by microanalysis, IR, ¹H NMR as well as ³¹P{¹H} NMR spectroscopy. The X-ray structures of ligand 1 and complex 1b are also reported.     

Sugar-based phosphite and phosphoroamidite ligands for the Cu-catalyzed asymmetric 1,4-addition to enones

A modular sugar-based phosphoroamidite L1–L5a–g and phosphite L6–L9a–g ligand library was tested in the asymmetric Cu-catalyzed 1,4-conjugate addition reactions of β-substituted (cyclic and linear) and β,β′-disubstituted (cyclic) enones. The selectivity depended strongly on the configuration of carbon atom C-3, the size of the sugar backbone ring, the flexibility of the ligand backbone, the substituents and configurations in the biaryl phosphoroamidite moieties a–g, the type of functional group attached to the ligand backbone and the substrate structure. Therefore, by carefully selecting the ligand parameters, enantioselectivities of up to 60% for cyclic substrates and 72% for linear ones were achieved.     

Unusual stabilization of cationic “M(η-allyl) (M = Pt, Pd) units by a dianionic cis-{Pt(C6F5)2(CCSiMe3)2} fragment

Chloride abstraction from [{M(η³ --- C₃H₅)Cl}_n] (M = Pt, n = 4 or M = Pd, n = 2) by (NBu₄)₂[cis-Pt(C₆F₅)₂(CCSiMe₃)₂] (1) gives rise to novel homo- and hetero-dinuclear zwitterionic derivatives (NBu₄) [{cis-Pt(C₆F₅)₂(CCSiMe₃)₂}M(η³-C₃H₅)] (M = Pt 2; M = Pd 3) which are formed by a M(η³-allyl)⁺ unit attached to both alkynyl ligands of the {cis-Pt(C₆F₅)₂(CCSiMe₃)₂}²⁻ fragment. The structure of 3 has been established by X-ray diffraction.     

Peroxisome proliferator-activated receptor �� agonist attenuates hepatic steatosis by anti-inflammatory mechanism

Although peroxisome proliferator receptor (PPAR)-α and PPAR-γ agonist have been developed as chemical tools to uncover biological roles for the PPARs such as lipid and carbohydrate metabolism, PPAR-δ has not been fully investigated. In this study, we examined the effects of the PPAR-δ agonist GW0742 on fatty liver changes and inflammatory markers. We investigated the effects of PPAR-δ agonist GW0742 on fatty liver changes in OLETF rats. Intrahepatic triglyceride contents and expression of inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and monocyte chemo-attractant protein-1 (MCP-1) and also, PPAR-γ coactivator (PGC)-1α gene were evaluated in liver tissues of OLETF rats and HepG2 cells after GW0742 treatment. The level of TNF-α and MCP-1 was also examined in supernatant of Raw264. 7 cell culture. To address the effects of GW0742 on insulin signaling, we performed in vitro study with AML12 mouse hepatocytes. Rats treated with GW0742 (10 mg/kg/day) from 26 to 36 weeks showed improvement in fatty infiltration of the liver. In liver tissues, mRNA expressions of TNF-α, MCP-1, and PGC-1α were significantly decreased in diabetic rats treated with GW0742 compared to diabetic control rats. We also observed that GW0742 had inhibitory effects on palmitic acid-induced fatty accumulation and inflammatory markers in HepG2 and Raw264.7 cells. The expression level of Akt and IRS-1 was significantly increased by treatment with GW0742. The PPAR-δ agonist may attenuate hepatic fat accumulation through anti-inflammatory mechanism, reducing hepatic PGC-1α gene expression, and improvement of insulin signaling.     

Syntheses and structures of doubly tucked-in titanocene complexes with tetramethyl(aryl)cyclopentadienyl ligands

Titanocene–bis(trimethylsilyl)ethyne complexes [Ti(η⁵-C₅Me₄R)₂(η²-Me₃SiCCSiMe₃)], where R=benzyl (Bz, 1a), phenyl (Ph, 1b) and p-fluorophenyl (FPh, 1c), thermolyse at 150–160°C to give products of double C---H activation [Ti(η⁵-C₅Me₄Bz){η³:η⁴-C₅Me₃(CH₂)(CHPh)}] (2a), [Ti(η⁵-C₅Me₄Bz){η³:η⁴-C₅Me₂Bz(CH₂)₂}] (2a′), [Ti(η⁵-C₅Me₄Ph){η³:η⁴-C₅Me₂Ph(CH₂)₂}] (2b), and [Ti(η⁵-C₅Me₄FPh){η³:η⁴-C₅Me₂FPh(CH₂)₂}] (2c). In the presence of 2,2,7,7-tetramethylocta-3,5-diyne (TMOD) the thermolysis affords analogous doubly tucked-in compounds bearing one η³:η⁴-allyldiene and one η⁵-C₅Me₄R ligand having TMOD attached by its C-3 and C-6 carbon atoms to the vicinal methylene groups adjacent to the substituent R (R=Bz (3a), Ph (3b), and FPh (3c)). Compound 3a is smoothly converted into air-stable titanocene dichloride [TiCl₂{η⁵-C₅Me₂Bz(CH₂CH(t-Bu)CH=CHCH(t-Bu)CH₂)}(η⁵-C₅Me₄Bz)] (4a) by a reaction with hydrogen chloride. Yields in both series of doubly tucked-in complexes decrease in the order of substituents: BzPh>FPh. Crystal structures of 1c, 2a, 2b, and 3b have been determined.     

Role of ligand conformation in the structural diversity of copper(II) and silver(I) coordination polymers containing the angular dipyridyl ligand bearing amide spacer

The new dipyridyl ligands N,N′-(methylenedi-p-phenylene)bis(pyridine-4-carboxamide), L1, and N,N′-(methylenedi-p-phenylene)bis(pyridine-3-carboxamide), L2, incorporating amide spacers have been synthesized and reacted with metal salts to give complexes of the types [Cu(L1)₂X₂]_∞ (X = Cl, 1 and X = Br, 2), {[Cu(L1)₂(DMF)](NO₃)₂}_∞, 3, {[Ag₂(L1)₂](SO₄)}_∞, 4, and {[Cu(L2)(DMSO)₂(NO₃)](NO₃)}_∞, 5. All compounds have been characterized by spectroscopic methods and their structures determined by X-ray crystallography.Complexes 1, 2 and 3 form 1-D double-stranded polymeric chains showing rhombic molecular squares with approximate dimensions of 16.95 × 19.13 Å² for 1, 17.03 × 19.06 Å² for 2 and 16.66 × 19.94 Å² for 3. Complex 4 forms infinite 1-D zigzag polymeric chains, which are interlinked through a series of Ag–O interactions to form wavy 1-D ladder like chains, and complex 5 forms 1-D sinusoidal chains. While the L1 ligands in complexes 1, 2 and 3 adopt the cis conformation and that in complex 4 adopts trans conformation, the L2 ligand in complex 5 adopts the trans-anti conformation. The ligand conformations also differ in the dihedral angles between the pyridyl and phenyl rings. All complexes exhibit emissions which may be tentatively assigned as intraligand (IL) π → π* transition.     

Natural Compound 3β,7β,25-trihydroxycucurbita-5,23(E)-dien-19-al from Momordica charantia Acts as PPARγ Ligand

Momordica charantia is a popular vegetable associated with effective complementary and alternative diabetes management in some parts of the world. However, the molecular mechanism is less commonly investigated. In this study, we investigated the association between a major cucurbitane triterpenoid isolated from M. charantia, 3β,7β,25-trihydroxycucurbita-5,23(E)-dien-19-al (THCB) and peroxisome proliferator activated receptor gamma (PPARγ) activation and its related activities using cell culture and molecular biology techniques. In this study, we report on both M. charantia fruit crude extract and THCB in driving the luciferase activity of Peroxisome Proliferator Response Element, associated with PPARγ activation. Other than that, THCB also induced adipocyte differentiation at far less intensity as compared to the full agonist rosiglitazone. In conjunction, THCB treatment on adipocytes also resulted in upregulation of PPAR gamma target genes expression; AP2, adiponectin, LPL and CD34 at a lower magnitude compared to rosiglitazone’s induction. THCB also induced glucose uptake into muscle cells and the mechanism is via Glut4 translocation to the cell membrane. In conclusion, THCB acts as one of the many components in M. charantia to induce hypoglycaemic effect by acting as PPARγ ligand and inducing glucose uptake activity in the muscles by means of Glut4 translocation.     

An evaluation of the Noyori system “in reverse”: Thermodynamic and kinetic parameters of secondary alcohol transfer dehydrogenation catalyzed by [(η-1-Pr-4-Me-C6H4)Ru(HN-CR′R″-CR′R″NTs)], R′ = H, Me; Ph, R″ = H, Me

The 16 electron ruthenium complexes [(η⁶-1-isopropyl-4-methyl-benzene)(X-N)Ru(II)], where X-N is 2-amido-1-ethoxide (2), 1-N-p-tosyl-1,2-diamido-ethane (3), 1-N-p-tosyl-1,2-diamido-benzene (7), 1-N-(p-tosyl)-1,2-diamido-1,1,2,2-tetramethyl-ethane (8) and 1-N-(p-tosyl)-1,2-diamido-meso-1,2-diphenyl-ethane (9) have been evaluated as catalysts for the transfer dehydrogenation of secondary alcohols to ketones in acetone and/or cyclohexanone solvent. Complexes 2 and 3 cannot be isolated and decompose under these conditions. In contrast complexes 7, 8 and 9 are supported by ligands designed to resist β-hydride elimination and can with the exclusion of oxygen be held in solution for weeks. Complex 7 is not active as a catalyst. Complexes 8 and 9 are highly air-sensitive and active as catalysts for transfer (de)hydrogenations under oxidizing and reducing conditions, respectively. There is no coordinative inhibition of the catalysts by the ketone solvent under oxidizing conditions, but both catalysts show a correlation between the reaction rates and the ΔG values of the reactions with reactions leading to α, β-unsaturated ketones proceeding faster. For all alcohol/ketone substrate pairs where the ketone is not α, β-unsaturated, the hydrogenation reactions under reducing conditions (iso-propanol solvent) are at least one order of magnitude faster than the corresponding dehydrogenation reaction under oxidizing conditions (acetone solvent).