Synthese von γ,γ'-Dihydroxysulfonen und γ-Hydroxy-γ'-ketosulfonen

Syntheses of γ,γ'-Dihydroxysulfones and γ-Hydroxy-γ'-ketosulfones Reduction of γ,γ'-diketosulfones 1 with dimethylaminoborane leads to γ,γ'-dihydroxysulfones 3 via γ-hydroxy-γ'-ketosulfones 2 . The influence of substituents on the ratio of the yields of 2 and 3 is investigated.     

Ungesättigte und halogenierte γ-Hydroxysulfone; Darstellung und Reaktivität

Unsaturated and Halogenated γ-Hydroxysulfones: Syntheses and Reactivities α,β-Unsaturated γ-hydroxysulfones 2 and β-bromo-γ-hydroxysulfones 4 are prepared from the corresponding keto derivatives by reduction with dimethylaminoborane. Addition of p-toluenethiol to the double bond of 2 takes place in the position β to that of the sulfonyl group. With bases an isomerisation of 2 to γ-ketosulfones 10 is observed. With primary or secondary amines Mannich bases are formed. β-Bromo-γ-hydroxysulfones 4 are cleaved by bases to yield 2 .     

Lactone, 10. Mitt. Zur Synthese N-heterocyclisch substituierter γ,γ-Diphenyl-γ-butyrolactone

Lactones, X: Synthesis of γ,γ-Diphenyl-γ-butyrolactones Substituted by N-Heterocycles Starting from 3 and 16 , syntheses of γ,γ-diphenyl-γ-butyrolactones with N-heterocycles at the α-position are described. Scope and limitation of the syntheses, tautomerism and stereochemistry of the products as well as spectroscopic results which are inconsistent with data from the literature are discussed.     

The role of dopaminergic systems in γ-hydroxybutyrate-induced electrocorticogram hypersynchronization in the rat

The effects of dopaminergic agonists and antagonists on the duration of hypersynchronization induced in the electrocorticogram (ecog) by γ-hydroxybutyrate (γ-HB) were tested in rats. Apomorphine (0·2–8 mg kg^?1), piribedil (2·5–10 mg kg^?1) and haloperidol (0·5–1 mg kg^?1) had no influence on the duration of the hypersynchrony. Amphetamine (1·5–6 mg kg^?1) inhibited the hypersynchrony, while (3,4-dihydroxyphenylamino)-2-imidazoline (DPI; 5, but not 1, mg kg^?1) prolonged its duration. The lack of effect of the dopamine receptor agonists apomorphine and piribedil, and the dopamine receptor blocker haloperidol, on the γ-HB-induced hypersynchrony might indicate that the inhibition of the impulse flow in the nigrostriatal dopamine system by γ-HB is not involved in the generation of the hypersynchrony. DPI is thought to be an agonist at a dopamine receptor not sensitive to apomorphine, and its facilitatory effect on γ-HB-hypersynchrony can be interpreted in terms of a possible involvement of another dopamine system in the ecog hypersynchrony induced by γ-HB. The antagonism of γ-HB by amphetamine is possibly due to an indirect stimulatory effect on noradrenergic receptors.     

Structure-activity studies of analogs of β, γ-methylene-ATP at P2X-purinoceptors in the rabbit ear central artery

Structure-activity studies using naphthylmethyl analogs of β, γ-methylene-ATP were conducted at the P_2X-purinoceptor that mediates contraction of the rabbit ear central artery by ATP, α, β-m-ATP. On the adenine base, substitution at the C²-position (WRC-0440) increased the agonist potency 2-fold and substitution at the C⁸-position (WRC-0431) did not change agonist potency, and both compounds had the same maximal response as β, γ-m-ATP, whereas substitution at the N⁶-position (WRC-0416) abolished activity. On the D-ribose sugar, substitution on the 2′-hydroxyl generated a partial agonist (WRC-0479), which had a maximal effect of only 39% of that of β-γ-m-ATP. Attempts to substitute the 3′-hydroxyls by naphthylmethyl failed, but substitution by p-methoxybenzyl (WRC-0617) did not change potency or the maximal response. Cyclic substitution of both the 2′- and 3′-hydroxyls by naphthylmethylidine (WRC-0498) had no effect on the agonist potency or the maximal response relative to β-γ-m-ATP. On the β, γ-methylenetriphosphonate chain, substitution on the methylene linkage by naphthylmethyl (WRC-0433) had no effect on agonist potency, but the maximal response increased to 122% that of β-γ-ATP. However, the contractile response to WRC-0433 was not desensitized by α, β-γ-ATP (contractile responses to all other agonists were abolished by α-β-γ-ATP pretreatment), but was blocked by the α₁ antagonist prazosin (10^?6 M). WRC-0433 appears to act at a prejunctional site that mediates ATP-induced release of norepinephrine. Purine nucleotides with substituents at the 2′-position of the ribose sugar could provide a lead to the generation of P_2X-purinoceptor antagonists. © 1995 Wiley-Liss, Inc.     

Synthesis and activity of the glutathione analogue γ-(L-γ-azaglutamyl)-L-cysteinyl-glycine

The backbone-modified glutathione analogue γ-(L-γ-azaglutamyl)-L-cysteinyl-glycine 7, characterized by the presence of a NHCONH urea linkage deriving from the replacement of the native Glu γ-CH₂ with the aza (NH) group, was synthesized and fully characterized by FAB-MS, ¹H- and ¹³C-NMR. Potential of 7 and its oxidized form 6 as γ-glutamyltransferase inhibitors was investigated. Both compounds 7 and 6 were found to be competitive inhibitors of hog kidney y-glutamyltransferase (EC 2.3.2.2.) by binding at the donor site: the reduced analogue is a more efficient inhibitor than glutathione of the γ-glutamyl transfer reaction. Inhibition at the acceptor site, which is also present, appears to be more complex. In particular, un-competitive inhibition is observed for compound 7. The results indicate that γ-azapeptides of type 7 may represent interesting targets in the search for stable inhibitors of γ-glutamyltransferases. © Munksgaard 1995.     

Massenspektrometrische Untersuchungen an isomeren α,β- und β, γ-ungesättigten Ketonen mit raumerfüllenden Substituenten

A Mass Spectrometric Study on Isomeric α,β- and β,γ-Unsaturated Ketones with Bulky Substituents The mass spectra of the α,β- and β,γ-unsaturated ketones 1-4 (scheme 1) are very different depending on the stereochemistry of the double bond. The E-configurated ketone 2 predominantly shows McLafferty fragmentation, whereas Z-configurated ketone 1 reveals ?-cleavage. In the β, γ-unsaturated ketones 3 and 4, mainly loss of the pertinent allyl radical by α-cleavage was observed.     

Synthesis and Activity of the Glutathione Analogue γ-(L-γ-Oxaglutamyl)-L-cysteinyl-glycine

An efficient synthesis of the backbone modified glutathione analogue γ-(L-γ-oxaglutamyl)-L-cysteinyl-glycine ( 7 ), characterized by the presence of an urethane O-CO-NH linkage replacing the γ-glutamylic CH₂CO-NH fragment is described. The new analogue has been fully characterized by ¹H- and ¹³C-NMR, and FAB-MS. Compound 7 was tested for inhibition of γ-glutamyl-transferase activity and was found to be a non-competitive inhibitor of hog kidney γ-glutamyltransferase (EC 2.3.2.2).     

Darstellung von γ-Hydroxysulfonen

Synthesis of γ-Hydroxysulfones A convenient synthesis of γ-hydroxysulfones 2 by reduction of the corresponding ketosulfones 1 with dimethylaminoborane is described. The influence of substituents on the reducibility is investigated. Some hydroxysulfones 2 are also prepared by reduction with monoborane in THF or by catalytic hydrogenation with Raney-Nickel.     

N-terminal sequences of γ-crystallins from the amphibian lens and their homology with γ-crystallins of other major classes of vertebrates

γ-Crystallins were isolated from the homogenate of frog eye lenses (Rana catesbeiana) by exclusion gel chromatography and further purified by cation-exchange chromatography. They were the only group of crystallins possessing free amino groups amenable to sequence analysis by Edman degradation. Comparison of the amino acid contents of the purified subfractions of γ-crystallins indicated their close relatedness in amino acid compositions and probably sequence homology as well. The amino-terminal sequence analysis of the purified γ-crystallin subfractions showed extensive homology between these amphibian γ-crystallin polypeptides themselves and also those from other vertebrate species, suggesting the existence of a multigene family and their close relatedness to γ-crystallins of other vertebrates. The sequence comparison of the γ-crystallin polypeptides from all major classes of vertebrates has provided strong support for the divergent evolution of γ-crystallin family.     

ENZYMATIC DETERMINATION OF PYRIDOXAL 5‘-PHOSPHATE WITH γ-CYANOAMINOBUTYRIC ACID APOSYNTHASE

A rapid alternative method is presented for the determination of pyridoxal 5′-phosphate (pyridoxal-P). The method involves the colorimetric analysis of thiocyanate liberated from S-cyanohomocysteine (Hcy(CN)) in the presence of cyanide when catalyzed by the pyridoxal-P dependent enzyme, γ-cyano-α-aminobutyric acid (γ-CNabu)-synthase (Hcy(CN) thiocyano-lyase [adding CN]). The rate of formation of thiocyanate is determined by the increase in absorbance at 470nm on treatment of the enzymatic reaction mixture with FeCl₃.     

Solid-phase synthesis of human osteocalcin by using a γ-carboxyglutamic acid derivative

Human osteocalcin, also called bone Gla protein (BGP), consisting of 49 amino acids with two to three γ-carboxyglutamate residues, was chemically synthesized for the first time by a novel solid-phase peptide synthesis. An l -enantiomer of N-tert-butyloxycarbonyl-γ,γ′-dicyclohexyl-γ-carboxyglutaniic acid was designed, prepared and utilized as a monomeric compound and proven to be useful for the solid-phase peptide synthesis of human osteocalcin. The synthesis and optical resolution of the γ-carboxyglutamic acid (Gla) derivative are first described, followed by the synthesis and characterization of Gla¹⁷-human osteocalcin.     

Agonist function of the recombinant α4β3δ GABAA receptor is dependent on the human and rat variants of the α4‐subunit

1. It is known that the α₄‐subunit is likely to occur in the brain predominantly in α₄β₃δ receptors at extrasynaptic sites. Recent studies have revealed that the α₁‐, α₄‐, γ₂‐ and δ‐subunits may colocalize extrasynaptically in dentate granule cells of the hippocampus. In the present study, we characterized a series of recombinant GABA_A receptors containing human (H) and rat (R) α₁/α₄‐, β₂/β₃‐ and γ_2S/δ‐subunits in Xenopus oocytes using the two‐electrode voltage‐clamp technique. 2. Both Hα₁β₃δ and Hα₄β₃γ_2S receptors were sensitive to activation by GABA and pentobarbital. Contrary to earlier findings that the α₄β₃δ combination was more sensitive to agonist action than the α₄β₃γ_2S receptor, we observed extremely small GABA‐ and pentobarbital‐activated currents at the wild‐type Hα₄β₃δ receptor. However, GABA and pentobarbital activated the wild‐type Rα₄β₃δ receptor with high potency (EC₅₀ = 0.5 ± 0.7 and 294 ± 5 μmol/L, respectively). 3. Substituting the Hα₄ subunit with Rα₄ conferred a significant increase in activation on the GABA and pentobarbital site in terms of reduced EC₅₀ and increased I_max. When the Hα₄ subunit was combined with the Rβ₃ and Rδ subunit in a heteropentameric form, the amplitude of GABA‐ and pentobarbital‐activated currents increased significantly compared with the wild‐type Hα₄β₃δ receptor. 4. Thus, the results indicate that the Rα₄β₃δ, Hα₁β₃δ and Hα₄β₃γ_2S combinations may contribute to functions of extrasynaptic GABA_A receptors. The presence of the Rα₄ subunit at recombinant GABA_A receptors containing the δ‐subunit is a strong determinant of agonist action. The recombinant Hα₄β₃δ receptor is a less sensitive subunit composition in terms of agonist activation.     

Synthese von 3-methylenmonosubstituierten 2-Oxo-tetrahydrofuranen durch Umsetzung von α-Keto-γ-lactonen mit Wittig-Reagenzien

Synthesis of 3-Methylenetetrahydrofuran-2-ones from α-Keto-γ-lactones with Wittig Reagents The synthesis of the 3-methylenetetrahydrofuran-2-ones 3a--q from the α-keto-γ-lactones 1a,b and the Wittig compounds 2a--h is described.     

Synthese von α-Trihalogenmethyl-γ-oxosulfonen

Synthesis of β-Trihalogenomethyl-γ-oxosulfones The title-compounds 6 are formed by reaction of sulfinic acids 4 with 1,1,1-trihalogen-2-buten-4-ones 1 and 1,1,1-trihalogen-2-chloro-4-butanones 8 , respectively, or by addition of thioles 3 to 1 and subsequent oxidation.     

Reaktionen α,β-ungesättigter γ-Oxosulfone mit Nucleophilen

Reactions of α,β-Unsaturated γ-Oxosulfones with Nucleophiles Bromination of the γ-oxosulfones 1 and subsequent dehydrohalogenation leads to the α,β-unsaturated γ-oxosulfones 3 . These products react with primary and secondary amines to yield the enaminoketones 7 . γ-Oxobissulfones 10 are formed from 3 by addition of the sulfinic acids 9 . Thioles 11 react with 3 to give the γ-oxomercaptosulfones 12 or the thioacetals 14 .     

Die Kondensation von γ-und δ-Oxo-carbonsäureester mit 1,2-, 1,3- und 1,4-Alkylendiaminen

Condensation of Esters of γ- and δ-Oxocarboxylic Acids with Alkylene-1,2,1,3- and 1,4-diamines. Esters of γ-and δ-Oxocarboxylic acids condense with alkylene-1,2-, 1,3-, and 1,4-diamines and yield bicyclic lactams (5) . The path of the reaction was studied by spectroscopic methods using ethyl levulinate and N-methyl-propylene-1,2-diamine. The first step is the formation of an “aminalester” by reaction of the CO-group of ethyl levulinate with alkylene diamine, followed by intramolecular ring closure.     

Structure–activity relationship of neuropeptide γ derived from mammalian and fish

Abstract: This study of relationship between structure and biologic activity was performed using five neuropeptide γs [NPγ; mammalian‐NPγ (M‐NPγ), trout‐NPγ (T‐NPγ), goldfish‐NPγ (G‐NPγ), bowfin‐NPγ (B‐NPγ), and shark‐NPγ (S‐NPγ)]. Circular dichroism (CD) spectra showed that all peptides took random structure in buffer solution. In neutral and acidic liposomes, M‐NPγ, T‐NPγ, B‐NPγ, and S‐NPγ still adopted random structure, while G‐NPγ had an α‐helical structure. The biologic activity of NPγs has been estimated by their effects on the intestinal motility and arterial relaxation. The intestinal motility was investigated with rat duodenum (RD), carp intestine (CI), and guinea‐pig ileum (GPI). The arterial relaxing effect was tested with guinea‐pig aorta (GPA) and rat mesenteric artery (RMA). In RD, the order of potency compared with the EC₅₀ value was M‐NPγ > S‐NPγ > B‐NPγ > G‐NPγ > T‐NPγ. G‐NPγ was the most contractile agent in CI. S‐NPγ was the most contractile agent in GPI. Using an arterial relaxing test, the order of potency was G‐NPγ > T‐NPγ > B‐NPγ > S‐NPγ > M‐NPγ in GPA, and all NPγs remarkably reduced relaxing activity in RMA. Despite their structural similarities to NPγs, G‐NPγ has high affinity to tachykinin receptor‐binding sites in GPA and CI, indicating an α‐helical structure may have a critical role for receptor binding. However, an α‐helical structure does not play a critical role in recognizing receptor‐binding sites in RD and GPI.     

Intestinal absorption pathway of γ-aminobutyric acid in rat small intestine

Intestinal absorption of γ-aminobutyric acid (GABA), as a model compound for γ-aminoacids, has not been extensively studied from the kinetic viewpoint. Since data from our laboratory suggested that some competition arises between intestinal absorption of β-alanine and GABA and since our intent was to maintain the aqueous stagnant diffusion layer in order to approach absorption tests to in vivo physiological conditions, a rat jejunum in situ study was undertaken in order to gain an insight into the mechanism of GABA absorption. In the present paper, results from assays using isotonic perfusion solutions with starting GABA concentrations ranging from 1 to 50 mM are reported. They show that the intestinal absorption of the γ-aminoacid can be apparently described as a specialized transport mechanism which obeys Michaelis-Menten and first-order kinetics. Parameter values found were V_m = 13.99 ± 2.37 mM h^?1, K_m = 3.87 ± 0.63 mM, and k_a(passive) = 0.362 ± 0.120 h^?1. Through the perfusion of 5 mM β-alanine solutions containing variable concentrations of GABA (from 5 to 50 mM), a partially competitive inhibition of β-alanine absorption was apparently characterized.     

Dithio- und Thionester, 57. Mitt.: Synthese N-geschützter β- und γ-Aminosäuredithioester und -thionester

Dithio and Thiono Esters, LVII: Synthesis of Dithio and Thiono Esters of N-Protected β- and γ-Amino Acids The N-Protected β-aminonitriles 1 were transformed into the imidoester or thiolimidoester hydrochlorides 2 or 3 according to Pinner and sulfhydrolyzed with H₂S to give the N-protected β-amino thiono esters 4 or dithio esters 5 . Alkylation of the amides 6 and thioamides 7 yields the iminium salts 8/9 and their sulfhydrolysis again 4/5 . By the first approach N-protected γ-amino nitriles 11 were converted into the γ-amino thiono esters 14 and dithio esters 15 .