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Long-term administration of lithium hydroxybutyrate (10 mg/kg, for 7 days) prevents the depression of avoidance behavior in rats and EEG alterations in the cortex and subcortical structures of rabbit brain induced by a single injection of 0.125 mg/kg reserpine.
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Agonists stimulate the release of myo-inositol from phosphatidylinositol (PtdIns) labelled in vivo with myo-[2-3H] inositol. In the presence of lithium, which inhibits myo-inositol-1-phosphatase, the compound which accumulates following the breakdown of pre-labelled PtdIns is inositol-1-phosphate. This indicates that the agonist-stimulated release of the head group from this lipid is not the result of inositol exchange and is due to phosphodiesterase activity. The total amount of 3H-labelled compounds released from PtdIns in the presence and absence of lithium is the same, which indicates the labelled compounds which are released are not re-incorporated. Agonist-induced release of myo-[2-3H] inositol can be used as a reliable indication of PtdIns breakdown in the exocrine pancreas.
Lithium and valproate are chemically unrelated compounds that are used to treat manic-depressive illness. Previously, we reported that lithium ions upregulate genes encoding proteins primarily associated with large dense core vesicles (LDCV) in nerve growth factor (NGF)-differentiated PC12 cells, but not in undifferentiated PC12 cells. Moreover, lithium did not alter the expression of proteins associated with small-clear, synaptic-like vesicles (SSV) in these cells. Based on these observations, we investigated whether valproate had actions similar to those of lithium in PC12 cells. Thus, undifferentiated or NGF-differentiated PC12 cells were exposed to lithium (1 mM) or valproate (1 mM) for 48 h. Extracts from these cells were submitted to semiquantitative Northern and Western analyses. In NGF-differentiated cells, both agents increased the expression of proteins associated with LDCV, the vesicular monoamine transporter 1 (VMAT1), and cysteine string protein (CSP). These same treatments did not alter the expression of proteins primarily associated with SSV, the vesicular acetylcholine transporter (VAChT), and synaptophysin (SY). Furthermore, neither drug affected the expression of these proteins in undifferentiated cells. Interestingly, secretion of (3)H-dopamine was increased in cells exhibiting the increase of VMAT1 and csp. Taken together, the convergent effects of these chemically diverse compounds suggest that altered dynamics of LDCV may play a vital role in the biochemical pathway, leading to the relief of the symptoms of manic depression.
Benzo[1,2,3]trichalcogenoles with two bromine atoms on the benzene ring, 5,6-dibromo-4,7-diethylbenzo[1,2,3]trichalcogenoles (1a) and (1b) (chalcogen: 1a = S; 1b = Se), were first prepared by treating 2,3,5,6-tetrabromo-1,4-diethylbenzene (TBDEB) with elemental sulfur or amorphous selenium in DBU at 140 degrees C (for 1a) and 100 degrees C (for 1b) for 24 h. The structures of 1a and 1b were verified by NMR spectroscopy, mass spectrometry, and elemental analysis. X-ray crystallographic analysis ultimately showed that the substitution reactions of TBDEB proceeded at the two adjacent bromine atoms. To apply 1a and 1b to construction of phthalocyanine derivatives with sulfur or selenium functional groups, 4,5-bis(benzylchalcogeno)-3,6-diethylphthalonitriles (5a) and (5b) as key intermediates were prepared by way of introduction of alkyl groups (2-cyanoethyl or 4-nitrophenethyl groups) on two chalcogen atoms, substitution of two bromine atoms with nitrile groups, and subsequent exchange of alkyl groups with benzyl groups. Compound 5a was treated with lithium in n-pentanol at 100 degrees C for 1 h to produce 2,3,9,10,16,17,23,24-octakis(benzylthio)-1,4,8,11,15,18,22,25-octaethylphthalocyanine (6a). A similar treatment of 5b in n-hexanol at 100 degrees C for 2 h gave phthalocyanine 6b. The structures of 6a and 6b were determined by (1)H NMR spectroscopy and MALDI-TOFMS. X-ray crystallographic analysis of 6a was also performed. The Q-band absorptions (lambda(max)) for 6a and 6b in UV-vis spectra were observed at 755 nm (log epsilon = 5.1) and 757 nm (log epsilon = 5.1), respectively, and their electrochemical properties were verified by cyclic voltammetry in dichloromethane with Ag/AgNO(3) as a reference electrode. Compounds 6a and 6b were further treated with lithium in THF/NH(3) at -78 degrees C and then with dibutyltin dichloride to produce phthalocyanine derivatives 8a and 8b with four dichalcogenastannole rings by way of octachalcogenate phthalocyanines 7a and 7b.
A new type of crown compounds (crownopaddlanes) bearing two cyclobutane rings were efficiently and selectively prepared by means of intramolecular [2 + 2] photocycloaddition of appropriate styrene derivatives, which was successfully carried out in cyclohexane under irradiation through a Pyrex filter. Crownopaddlanes 4a, 5, and 6 exclusively and quantitatively extracted Li(+) on the solid-liquid extraction. Upon the competitive extraction, 4a showed the highest selectivity toward Li(+) over Na(+) and K(+) (Li(+)/Na(+) = 610, Li(+)/K(+) = 976). The structural factors working in the complexation of the crownopaddlane were examined by X-ray crystallographic analysis.
Lipid metabolism has been considered recently as a novel target for cancer therapy. In this field, lithium gamma-linolenate (LiGLA) is a promising experimental compound for use in the treatment of human tumours. In vivo and in vitro studies allowed us to assess the metabolism of radiolabelled LiGLA by tumour tissue and different organs of the host. In vitro studies demonstrated that human pancreatic (AsPC-1), prostatic (PC-3) and mammary carcinoma (ZR-75-1) cells were capable of elongating GLA from LiGLA to dihomo-gamma-linolenic acid (DGLA) and further desaturating it to arachidonic acid (AA). AsPC-1 cells showed the lowest delta5-desaturase activity on DGLA. In the in vivo studies, nude mice bearing the human carcinomas were given Li[1-(14)C]GLA (2.5 mg kg(-1)) by intravenous injection for 30 min. Mice were either sacrificed after infusion or left for up to 96 h recovery before sacrifice. In general, the organs showed a maximum uptake of radioactivity 30 min after the infusion started (t = 0). Thereafter, in major organs the percentage of injected radioactivity per g of tissue declined below 1% 96 h after infusion. In kidney, brain, testes/ovaries and all three tumour tissues, labelling remained constant throughout the experiment. The ratio of radioactivity in liver to tumour tissues ranged between 16- and 24-fold at t = 0 and between 3.1- and 3.7-fold at 96 h. All tissues showed a progressive increase in the proportion of radioactivity associated with AA with a concomitant decrease in radiolabelled GLA as the time after infusion increased. DGLA declined rapidly in liver and plasma, but at a much slower rate in brain and malignant tissue. Seventy-two hours after the infusion, GLA was only detected in plasma and tumour tissue. The sum of GLA + DGLA varied among tumour tissues, but it remained 2-4 times higher than in liver and plasma. In brain, DGLA is the major contributor to the sum of these fatty acids. Data showed that cytotoxic GLA and DGLA, the latter provided either by the host or by endogenous synthesis, remained in human tumours for at least 4 days.
A combination of density functional calculations (B3LYP/6-31+G(d) level of theory) and experimental investigations (NMR and cryoscopic measurements) lead to structural assignments in solution for a series of three sulfur stabilized allyllithium compounds 1-3. All three lithium species are monomers in THF under the experimental conditions studied here and exist exclusively in an endo conformation. Increasing the oxidation state of sulfur (thiol --> sulfoxide --> sulfone) causes a change in the solution state structure of the allyllithium compounds. In the case of 1-thiophenylallyllithium 1, a fast equilibrium between two eta(1)-species is present with the equilibrium favoring the eta(1) C(alpha)-Li contact ion pair. The preference for this conformation can be attributed to the charge stabilizing properties of the sulfur substituent. For the lithiated sulfoxide 2, this equilibrium is frozen on the NMR time scale and two different lithium species (a eta(1) C(alpha)-Li and a eta(1) C(gamma)-Li contact ion pair), each possessing an intramolecular Li-O contact, coexist in d(8)-THF. In the case of the lithiated sulfone 3, several solvated conformations are in rapid equilibrium with each other on the NMR time scale in solution. The presence of two chelating oxygen atoms allows the lithium to form a OLiO scissor-like contact ion pair that competes with the eta(1) C(alpha)-Li and the eta(1) C(gamma)-Li contact ion pairs also calculated for compound 3.
[figure: see text] The direct opening at the bridgehead of oxabicyclo[3.2.1]octenes employing silyl ketene acetals in 4.0-5.0 M lithium perchlorate in diethyl ether has been realized, which gives rise to highly functionalized cycloheptadienes that can be further manipulated for use in natural product synthesis. The bridgehead opening reaction has been employed in the construction of the C(19)-C(27) fragment of Rifamycin S.
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A reinvestigation of the radiation protection activity of S-[2-[(2'-carbamylethyl)amino]ethyl] lithium hydrogen phosphorothioate (4a) revealed that this compound possessed good (70% protection at a dose of 600 mg/kg) activity. The thione and imino bioisosteres of 4, S-[2-(2'-thiocarbamylethylamino)ethyl] lithium hydrogen phosphorothioate (13a) and S-[2-(2'-amidinoethylamino)ethyl] phosphorothioic acid (18b) showed 100% protection at doses of 300 and 150 mg/kg, respectively. The N-methyl (4b) and tert-butyl (4c) analogues of amide 4a, the N-methyl (13b) analogue of the thioamide 13a, the N-methyl (18a) analogue of amidine (18b), and the cyclic amidine S-[2-[[2'-(4,5-dihydroimidozoyl)ethyl]amino]ethyl] lithium hydrogen phosphorothioate (21) all showed 80% protection at the highest dose tested.
Synthesis of [3 alpha-3H]7-dehydrocholesterol is described via protection of the 5,7-diene system in 7-dehydrocholesterol as the Diels-Alder adduct with 4-phenyl-1,2,4-triazoline-3,5-dione followed by oxidation of the hydroxyl group to give the 3-oxo adduct. Reduction of the keto adduct with [3H]sodium borohydride produced the adduct of [3 alpha-3H]7-dehydrocholesterol from which the radiolabeled sterol was obtained via treatment with lithium aluminum hydride. The advantage of the method is that highly labeled [3 alpha-3H]7-dehydrocholesterol can be prepared. Further, unlike 7-dehydrocholesterol, its adduct with 4-phenyl-1,2,4-triazoline-3,5-dione is stable and can be stored. This allows the preparation of small batches of [3 alpha-3H]7-dehydrocholesterol for immediate use in biological experiments, and losses due to decomposition of excess radiolabeled 7-dehydrocholesterol are minimized.
[formula: see text] A new method for the synthesis of alpha,beta-unsaturated lactones from beta-acetoxy aldehydes by reaction with the lithium enolate of methyl acetate was developed. The reaction is relatively insensitive to structural changes in the aldehyde substrates. The process was extended to the synthesis of five-ring lactones from alpha-acetoxy aldehydes. Experimental evidence regarding the mechanism of this one-pot transformation was obtained. The observations are consistent with a pathway involving an initial aldol condensation with subsequent acyl migration, lactonization, and beta-elimination and not an enolate equilibration-aldol mechanism.
5 alpha-(17R,20R)-14,15-Secocholestane (12) was synthesized from cholesterol (1) in 12 steps. The key intermediate, 5 alpha-cholest-14-en-3 beta-yl acetate (4), underwent ozonization, reduction, hydrolysis, and oxidation to provide 5 alpha-14,15-secocholesta-3,14,15-trione (8). One of the Clemmensen reduction products of 8 is 5 alpha(17R,20R)-14,15-secocholest-15-ol (11); treatment of the alcohol (11) with tosyl chloride and subsequent reduction with lithium aluminum hydride yielded the target molecule (12).
The effects of saccharin concentration on the stimulus control by a compound stimulus consisting of morphine, saccharin (0.01, 0.03, or 0.10%, wt/vol), and a ball bearing drinking nozzle in a discriminated taste aversion (DTA) procedure were examined in rats (Rattus norvegicus). In paired rats injections of lithium followed presentation of this compound stimulus, whereas in unpaired rats saline injections followed this stimulus. DTA acquisition was more rapid at higher saccharin concentrations. In testing with each individual stimulus element, stimulus control was clearly exerted by all 3 stimulus elements. When another stimulus element was presented jointly with saccharin, behavioral control was similar to that of saccharin alone. Behavioral control by saccharin increased with saccharin concentration. However, behavioral control by the 2 other stimulus elements was relatively unaffected when the saliency of the saccharin element was increased.
Exchange of intracellular sodium for extracellular lithium readily occurs in vascular smooth muscle, but the mechanism of this exchange is not known. These studies examined whether a sodium-lithium countertransport system was present in the cell membrane of vascular smooth muscle. A sarcolemmal-enriched vesicle preparation was obtained from canine superior mesenteric artery via a magnesium aggregation and differential centrifugation technique. An outwardly directed gradient for lithium stimulated 22Na uptake by the vesicles, and an inwardly directed gradient for lithium stimulated 22Na efflux. These effects were not due to an alteration in membrane potential, and sodium uptake was not stimulated by lithium in the absence of a gradient for lithium. The lithium gradient-stimulated component of sodium uptake was not affected by a change in membrane potential and was insensitive to ouabain. Both sodium-lithium exchange and sodium-proton exchange in sarcolemmal-enriched vesicles were inhibited by two compounds that inhibit the sodium-lithium countertransport system in red cells, phloretin and quinidine. Ethylisopropylamiloride also inhibited both sodium-lithium exchange and sodium-proton exchange in the vesicles. In support of the possibility that sarcolemmal sodium-lithium exchange and sodium-proton exchange are mediated by a single cation exchange mechanism with affinity for sodium, lithium, and protons, we found that an inwardly directed sodium or lithium gradient stimulated proton efflux, and that the stimulation of sodium efflux by external lithium or protons was not additive. It is concluded from these studies that sarcolemmal vesicles from canine superior mesenteric artery contain an electroneutral, phloretin, quinidine, and ethylisopropylamiloride inhibitable sodium-lithium exchange transport system.(ABSTRACT TRUNCATED AT 250 WORDS)
An improved synthesis of N2-protected-3'-azido-2',3'-dideoxyguanosine 20 and 23 is described. Deoxygenation of 2'-O-alkyl (and/or aryl) sulfonyl-5'-dimethoxytritylguanosine coupled with [1,2]-hydride shift rearrangement gave protected 9-(2-deoxythreo-pentofuranosyl)guanines (10, 12 and 16). This rearrangement was accomplished in high yield with a high degree of stereoselectivity using lithium triisobutylborohydride (L-Selectride). Compounds 10, 12 and 16 were transformed into 3'-O-mesylates (18 and 21), which can be used for 3'-substitution. The 3'-azido nucleosides were obtained by treatment of 18 and 21 with lithium azide. This procedure is reproducible with a good overall yield.
UNLABELLED: Concern persists regarding the production of carbon monoxide (CO) and Compound A from the action of carbon dioxide (CO(2)) absorbents on desflurane and sevoflurane, respectively. We tested the capacity of eight different absorbents with various base compositions to produce CO and Compound A. We delivered desflurane through desiccated absorbents, and sevoflurane through desiccated and moist absorbents, then measured the resulting concentrations of CO from the former and Compound A from the latter. We also tested the CO(2) absorbing capacity of each absorbent by using a model anesthetic system. We found that the presence of potassium hydroxide (KOH) and sodium hydroxide (NaOH) increased the production of CO from calcium hydroxide (Ca[OH](2)) but did not consistently affect production of Compound A. However, the effect of KOH versus NaOH was not consistent in its impact on CO production. Furthermore, the effect of KOH versus NaOH versus Ca(OH)(2) was inconsistent in its impact on Compound A production. Two absorbents (Amsorb) [Armstrong Medica, Ltd, Coleraine, Northern Ireland], composed of Ca(OH)(2) plus 0.7% polyvinylpyrrolidine, calcium chloride, and calcium sulfate; and lithium hydroxide) produced dramatically lower concentrations of both CO and Compound A. Both produced minimal to no CO and only small concentrations of Compound A. The presence of polyvinylpyrrolidine, calcium chloride, and calcium sulfate in Amsorb appears to have suppressed the production of toxic products. All absorbents had an adequate CO(2) absorbing capacity greatest with lithium hydroxide. IMPLICATIONS: Production of the toxic substances, carbon monoxide and Compound A, from anesthetic degradation by carbon dioxide absorbents, might be minimized by the use of one of two specific absorbents, Amsorb (Armstrong Medica, Ltd., Coleraine, Northern Ireland) (calcium hydroxide which also includes 0.7% polyvinylpyrrolidine, calcium chloride, and calcium sulfate) or lithium hydroxide.