A model of the human M2 muscarinic acetylcholine receptor

The M₂ muscarinic acetylcholine receptor belongs to the family of rhodopsin like G-Protein Coupled Receptors. This subtype of muscarinic receptors is of special interest because it bears, aside from an orthosteric binding site, also an allosteric binding site. Based on the X-ray structure of bovine rhodopsin a complete homology model of the human M₂ receptor was developed. For the orthosteric binding site point mutations and binding studies with different agonists and antagonists are available. This knowledge was utilized for an initial verification of the M₂ model. Allosteric modulation of activity is mediated by structurally different ligands such as gallamine, caracurine V salts or W84 (a hexamethonium-derivative). Caracurine V derivatives with different affinities to M₂ were docked using GRID-fields. Subsequent molecular dynamics simulations yielded different binding energies based on diverse electrostatic and lipophilic interactions. The calculated affinities are in good agreement to experimentally determined affinities.     

Surface properties of new virginiamycin M1 derivatives

Three kinds of derivatives of the M₁ factor of virginiamycin have been synthesised: esters with long chain fatty acids, oximes with modified polar amino acids and bis-derivatives with both the ester and oxime function. The study of the surface tension time dependence of M₁ and its derivatives has shown that it is necessary to enhance simultaneously the hydrophobicity and the hydrophilicity of M₁ to render M₁ surface-active. A structure/function relationship study of the surface-active bis-derivatives has shown that enhancing the hydrophobicity of the molecule led to slower adsorption kinetics, higher stability of the monolayers formed and a better capacity to penetrate a membrane model. The repulsive electrostatic forces due to the presence of charges on the amino acids linked to M₁ lead to higher surface tensions, a greater molecular area at the interface and lower penetration into a membrane model.This study has demonstrated that modifying systematically the hydrophobicity and hydrophilicity of a non surface-active molecule allows the production of surface-active derivatives.     

Experimental and theoretical studies on three spiromuscar-3-one M1 agonist derivatives

Muscarone analogues are compounds that have been proposed for the prevention or treatment of senile dementias. ARL-16607 (I), ARL-15467 (II), ARL-14995 (III) and YM-796 (IV) are spiromuscar-3-one derivatives and behave as muscarinic M₁ agonists, with different binding selectivity and efficacy at the M₁ receptors. In this work, we have elucidated the solid-state structures of I-III and compared the results obtained with the data available in the literature for IV.The solid-state arrangements of I-IV have then been used to input a series of theoretical calculations. For each molecule, eight conformations have been modeled and the obtained structures (1-32) have been submitted to a series of molecular dynamics/simulated annealing and molecular mechanics calculations aimed to explore the conformational freedom of the spiromuscar-3-one moiety. Some hints about the reactivity of I-IV have been obtained by performing Hartree-Fock, density functional theory and semiempirical quantum mechanics calculations. These studies analyzed the properties of the frontier orbitals and of the molecular electrostatic potential of I-IV.The information gained has been used to explain the better efficacy and poorer selectivity shown by III. Our results suggest that the behavior of III is due to its smaller size, the features of its molecular surface, the shape of its electrostatic potential and the orientation of its reactive domains.     

A convenient route to carbon-substituted derivatives of nido-5,6-C2B8H12

An alternative route to the parent nido-5,6-C₂B₈H₁₂ dicarbaborane is reported together with a convenient synthesis of its carbon-substituted derivatives. The method is based on reactions between 4-(Me₂S)-arachno-B₉H₁₃ and alkynes R¹R²C₂ (where R¹R²=H,H; Me, Me; Ph,H, and Ph,Ph) in toluene at reflux. The characteristic reaction mode is a dicarbon insertion into the 9-vertex arachno cluster to produce a series of the 5,6-R¹R²-nido-5,6-C₂B₈H₁₀ species combined with concomitant elimination of one {BH} vertex. The products were characterised by high-field ¹H and ¹¹B NMR spectroscopy and mass spectrometry associated with [¹¹B–¹¹B]-COSY and ¹H{¹¹B(selective)} measurements that permitted complete assignments of all resonances to individual cluster {BH} units.     

SmI2 mediated synthesis of 2,3-disubstituted indole derivatives

A novel preparation of 2,3-disubstituted indole derivatives was achieved through SmI₂ induced intramolecular reductive coupling reactions of acylamido carbonyl compounds.     

A combination of flow and batch mode processes for the efficient preparation of mGlu2/3 receptor negative allosteric modulators (NAMs)

Benzodiazepinones are privileged scaffolds with activity against multiple therapeutically relevant biological targets. In support of our ongoing studies around allosteric modulators of metabotropic glutamate receptors (mGlus) we required the multigram synthesis of a β-ketoester key intermediate. We report the continuous flow synthesis of tert-butyl 3-(2-cyanopyridin-4-yl)-3-oxopropanoate and its transformation to potent mGlu_2/3 negative allosteric modulators (NAMs) in batch mode.     

A chemoselective ligation for the synthesis of amino acid derivatives of virginiamycin M1

An efficient chemoselective ligation approach using an oxime bond was developed for the synthesis of amino acid derivatives of virginiamycin M₁, a highly sensitive streptogramin antibiotic.     

Highly selective hydroarylation of propiolic acid derivatives using a PtCl2/AgOTf catalytic system

Hydroarylation of propiolic acid derivatives with arenes in trifluoroacetic acid efficiently proceeded in the presence of PtCl₂/AgOTf catalyst to give cis-cinnamic acid derivatives in good to high yields. This PtCl₂/AgOTf-catalyzed reaction did not afford any 4-arylbuta-1,3-diene-1,3-dicarboxylic acid derivatives formed by Pd(OAc)₂-catalyzed hydroarylation. The specific optimization of the catalytic hydroarylation and application to electron-rich arenes are reported.     

A new synthetic route to compounds of the AFDX-type with affinity to muscarinic M2-receptor

[3-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)-propyl]dimethyl-{6-[(1-{2-[(6-oxo-5,6-dihydro-benzo[e]pyrido[3,2-b][1,4]diazepine-11-carbonyl)amino]ethyl}piperidin-2-yl-methyl)-propylamino]hexyl}ammonium bromide a hybride containing a fragment of the antagonist of muscarinic receptor AFDX-384 and a W84 moiety known as allosteric modulator of antagonist binding, was synthesized in a divergent synthesis starting from pipecolic acid, phthalic anhydride and 3-amino-2-chloropyridine. This new microwave assisted route is very convenient and allows to modify the piperidine ring, the benzodiazepine system, the phthalimide moiety and the chains connecting the ring systems. Yields and reproducibility were satisfying.     

Pentafluoro-λ-sulfanyl (SF5) perfluoroalkyl iodides-synthesis and reaction with ethylene and tetrafluoroethylene : Crystal structure of SF5(CF2)4CH2CH2I

A series of reactions between SF₅CF₂CF₂I and SF₅(CF₂)₄I with F₂CCF₂ was carried out in an effort to find the most effective methods for chain-extension. Also, for the first time, SF₅(CF₂)₈I and SF₅(CF₂)₁₀I have been prepared and isolated. The reaction conditions for the addition of H₂CCH₂ were also investigated. A determination of the crystal structure of the SF₅(CF₂)₄CH₂CH₂I has been carried out: the crystal system is monoclinic, with space group P2(1)/n and a=23.465(5) Å; b=6.0971(12) Å; c=44.892(9) Å; α=90°; β=99.38(3)°; γ=90°; Z=20.     

Synthesis of functional derivatives of the [3,3′-Co(1,2-C2B9H11)2] anion

A series of various functional derivatives of the cobalt bis(1,2-dicarbollide) anion [8-XCH₂CH₂OCH₂CH₂O-3,3′-Co(1,2-C₂B₉H₁₀)(1′,2′-C₂B₉H₁₁)]⁻ (X=OH, NH₂, and CH(NH₂)COOH) were prepared by the ring-opening reactions of [8-O(CH₂CH₂)₂O-3,3′-Co(1,2-C₂B₉H₁₀)(1′,2′-C₂B₉H₁₁)] with different nucleophiles followed by functional group interconversion reactions. Acidic hydrolysis of [8-NCCH₂CH₂OCH₂CH₂O-3,3′-Co(1,2-C₂B₉H₁₀)(1′,2′-C₂B₉H₁₁)]⁻ resulted in the shorter-chain alcohol [8-HOCH₂CH₂O-3,3′-Co(1,2-C₂B₉H₁₀)(1′,2′-C₂B₉H₁₁)]⁻. Structures of (Bu₄N)[8-AcNHC(COOEt)₂CH₂CH₂OCH₂CH₂O-3,3′-Co(1,2-C₂B₉H₁₀)(1′,2′-C₂B₉H₁₁)] and [8-(1-C₅H₅N)CH₂CH₂OCH₂CH₂O-3,3′-Co(1,2-C₂B₉H₁₀)(1′,2′-C₂B₉H₁₁)] were determined by the single crystal X-ray diffraction method. Perspectives of application of functionalized cobalt bis(1,2-dicarbolide) derivatives in nuclear medicine are discussed.     

A novel and green synthesis of kojic acid derivatives in ionic liquid [bmim]BF4

A series of 3-(3-hydroxy-6-methyl-4-oxo-4H-pyran-2-yl)-3-phenylpropanamide derivatives were synthesized efficiently by one-pot condensation of aromatic aldehydes, meldrum’s acid, allomaltol, and ammonium acetate in ionic liquid [bmim]BF₄. The novel synthesis method offers the advantage of operational simplicity, mild reaction conditions, short reaction time, higher yields, and environmental friendliness.     

Alkynethiolate ligands in the syntheses of iron carbonyl derivatives. Crystal structure of [(η-C5H5)Fe(CO)2(SCCSiMe3)]

The complexes [(η⁵-C₅H₅)Fe(CO)₂(SCCR)] (R=^tBu, SiMe₃) have been obtained by reaction of [(η⁵-C₅H₅)Fe(CO)₂I] and the corresponding LiSCCR. These are the first examples of mononuclear iron compounds containing alkynethiolate ligands. The crystal structure of [(η⁵-C₅H₅)Fe(CO)₂(SCCSiMe₃)] has been determined by X-ray diffraction. The role of [(η⁵-C₅H₅)Fe(CO)₂(SCCSiMe₃)] as a metalloligand in its reactions with metal carbonyls has been explored.     

A novel ferrimagnetic irido-cuprate: IrSr2GdCu2O8

We have performed an investigation of the structural, microstructural and magnetic properties of the new compound IrSr₂GdCu₂O₈. The sample was prepared under high temperature (∼1393 K) and high-pressure conditions (∼60 Kbars) in a Belt type apparatus. X-ray diffraction (XRD) analysis shows that this irido-cuprate is isostructural with the corresponding Ru-1212 phase. Structurally, this material shows an interesting hierarchy of ordering phenomena, whose observation actually depends on the technique used to analyze the material: from a “simple” cell a_p×a_p×3a_p which is supported by XRD, through a “diagonal” one, as seen by SAED, to a microdomain texture of this last one cell supported by HREM. A ferrimagnetic Ir^IV-Gd^III spin ordering is observed below 15 K. The iridium oxidation state seems to be +4.     

Positive and negative AMPA receptor modulators based on tricyclic bispidine derivative: Minor structural change inverts the type of activity

Two new potent AMPA receptor allosteric modulators, 6-(1,3-benzodioxol-5-yl)-1,11-dimethyl-3,6,9-triazatri-cyclo[7.3.1.1^3,11]tetradecane-4,8,12-trione and -4,8-dione were synthesized from 1,3-benzodioxol-5-amine and the corresponding 3,7-dichloroacetyl-3,7-diazabicyclo[3.3.1]-nonanes. In a wide concentration range (10^?12–10^?7 m), the 12-oxo derivative acts as a positive modulator causing the potentiation of the kainate-induced AMPA receptor currents with maximum potentiation at 1 nm (62%) while its analogue without a ketone group has significant (up to 40%) negative modulator effect. Their tentative mechanisms of action were analyzed by means of molecular modelling     

Phenylmercury(II) derivatives of tetraorganodichalcogenoimidodiphosphorus acids. Crystal and molecular structure of [PhHg{(OPR2)(SPPh2)N}]2 (R=Me, Ph)

The reactions between PhHgCl or PhHgAc and M[(XPR₂)(YPR′₂)N] (M=Na, K; X, Y=O, S; R, R′=Me, Ph, OEt), in 1:1 molar ratio, have been investigated. PhHg[(XPR₂)(YPR′₂)N] derivatives were isolated as microcrystalline powders and were characterised using IR and NMR (¹H, ¹³C and ³¹P) spectroscopy and mass spectrometry. The molecular structure of PhHg[(OPR₂)(SPPh₂)N] [R=Me (1), Ph (2)] was investigated by X-ray diffraction. In the monomeric unit, PhHg[(OPR₂)(SPPh₂)N], the mercury atom forms the primary bonds with the carbon of the phenyl group and the sulfur atom of the phosphorus ligand [Hg(1)-S(1) 2.405(1) Å for 1, 2.398(2) Å for 2]. These primary bonds are significantly deviated from the expected linear arrangement [C(1)-Hg(1)-S(1) 166.4(2)° for 1, 165.0(2)° for 2]. Both compounds exhibit dimeric associations in the crystal through S,O-bridging organophosphorus ligands [Hg(1)-O(1) 2.556(4) Å for 1, 2.588(4) Å for 2], thus resulting in a distorted T-shaped arrangement of the CHgSO coordination core.. The formation of a 12-membered Hg₂O₂S₂P₄N₂ ring with different conformation in 1 and 2, respectively, results in different additional chalcogen atoms being in the proximity of the metal atom. Weak transannular Hg?O [2.753(4) Å] are also established in 1, leading to a tricyclic ladder structure with a planar central Hg₂O₂ ring.     

UTa2O(S2)3Cl6: A ribbon structure containing a heterobimetallic 5d-5f M3 cluster

A new solid-state compound containing a heterobimetallic cluster of U and Ta, UTa₂O(S₂)₃Cl₆, has been synthesized and its structure has been characterized by single-crystal X-ray diffraction methods. UTa₂O(S₂)₃Cl₆ was synthesized from UCl₄ and Ta_1.2S₂ at 883 K. The O is believed to have originated in the Ta_1.2S₂ reactant. The compound crystallizes in the space group P1¯ of the triclinic system. The structure comprises a UTa₂ unit bridged by μ₂-S₂ and μ₃-O groups. Each Ta atom bonds to two μ₂-S₂, the μ₃-O, and two terminal Cl atoms. Each U atom bonds to two μ₂-S₂, the μ₃-O, and four Cl atoms. The Cl atoms bridge in pairs to neighboring U atoms to form a ribbon structure. The bond distances are normal and are consistent with formal oxidation states of +IV/+V/-II/-I/-I for U/Ta/O/S/Cl, respectively. The optical absorbance spectrum displays characteristic transition peaks near the absorption edge. Density functional theory was used to assign these peaks to transitions between S^1- valence-band states and empty U 5f-6d hybrid bands. Density-of-states analysis shows overlap between Ta 5d and U bands, consistent with metal-metal interactions.     

Crystal structure and characterization of the bis(n-benzyl-benzotriazole-n3)-dichloro Co(II) complex: CoCl2(C6H4N3CH2Ph)2

The structure of [CoCl₂(C₆H₄N₃CH₂Ph)₂] has been determined by X-ray crystallography. It is also characterized by elemental analysis, IR and electronic spectroscopy, and by thermogravimetric differential thermal analysis. It crystallizes in the monoclinic system, space group C2/c, with lattice parameters a = 16.133(3) , b = 11.355(2) , c = 15.637(3) , = 117.22(3)°, and Z = 8. The crystal structure of the title compound consists of monomeric molecules of [CoCl₂(C₆H₄N₃CH₂Ph)₂] with slightly distorted tetrahedron geometry for the CoCl₂N₂ chromophore. The thermal gravimetry (TG) data indicate that there are four decomposition steps with five endothermic peaks. The final product of the thermal decomposition is CoCl₂. Elemental analysis and the electronic and IR spectra are in agreement with the structural data.Original Russian Text Copyright © 2004 by F. Jian, H. Wang, and H. XiaoTranslated from Zhurnal Strukturnoi Khimii, Vol. 45, No. 4, pp. 723–728, July–August, 2004.This revised version was published online in April 2005 with a corrected cover date.     

Synthesis and Characterization of N3P3(O2C12H8)2(OC6H4Si(CH3)3)(OC6H4Br) and Its Conversion to Nanostructured Si Material

A new silicated cyclotriphosphazene N₃P₃(O₂C₁₂H₈)₂(OC₆H₄Si(CH₃)₃)(OC₆H₄Br) 1 has been synthesized and characterized. The solid state pyrolysis of 1 in air gives a nanostructured SiP₂O₇ 3D network. The morphology of the network strongly depends on the temperature of the pyrolysis. Spinal-like columns and ring-shaped SiP₂O₇ are formed at 800 °C, while, at 600 °C, fused grains of about 300 nm were observed. Based on air TG and DSC thermal studies, we propose the mechanism of formation for the nanostructured network.     

Thermogravimetry of the analytical precipitates M2Pb[Co(NO2)6] AND MPb[Co(NO2)6]

Thermogravimetric studies are reported for analytical precipitates of the types MPb[Co(NO₂)₆] and M₂Pb[Co(NO₂)₆], where M represents the univalent cations NH⁺₄, K⁺, Rb⁺, Cs⁺, and Tl⁺. Compounds of the latter series are consitently more stable to higher temperatures. For either series increasing the radius of M increases thermal stability. Decomposition to temperatures approaching 500°C involves some four separate processes.