Effects of the 5-HT(1A) agonist (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) on cocaine choice in cynomolgus monkeys

Drugs that alter brain serotonin (5-HT) function can modulate the behavioral effects of cocaine, but the underlying receptor mechanisms are poorly understood. The present study examined the effects of the selective 5-HT1A receptor agonist (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 0.01-0.1 mg/kg, i.v.) on cocaine self-administration in the context of a choice procedure. Five adult male cynomolgus monkeys self-administered cocaine (saline, 0.003-0.03 mg/kg per injection) under a concurrent fixed-ratio 50 schedule of food (1-g banana-flavored pellets) and cocaine presentation. Allocation of responses to the cocaine-associated lever (cocaine choice) increased in a dose-related manner from < or =20% of total responses when saline or 0.003 mg/kg per injection cocaine was the alternative to food to > or =75% when 0.03 mg/kg per injection cocaine was available. In four of five monkeys, when choice was between a low cocaine dose and food, 0.01 mg/kg 8-OH-DPAT increased injection-lever responding. At cocaine doses which occasioned > or =75% cocaine choice, 8-OH-DPAT did not alter response allocation. In the fifth monkey, 8-OH-DPAT only decreased injection-lever responding. When choice was between saline and food, 8-OH-DPAT did not reliably shift responding to the injection lever, except at doses that disrupted operant performance. These results suggest that a 5-HT1A receptor agonist can increase the reinforcing strength of a low cocaine dose relative to a concurrently available non-drug reinforcer.

Analysis of molecular determinants of affinity and relative efficacy of a series of R- and S-2-(dipropylamino)tetralins at the 5-HT1A serotonin receptor

1 Factors influencing agonist affinity and relative efficacy have been studied for the 5-HT1A serotonin receptor using membranes of CHO cells expressing the human form of the receptor and a series of R-and S-2-(dipropylamino)tetralins (nonhydroxylated and monohydroxylated (5-OH, 6-OH, 7-OH, 8-OH) species). 2 Ligand binding studies were used to determine dissociation constants for agonist binding to the 5HT(1A) receptor: (a) K-i values for agonists were determined in competition versus the binding of the agonist [H-3]-8-OH DPAT. Competition data were all fitted best by a one-binding site model. (b) K-i values for agonists were also determined in competition versus the binding of the antagonist [H-3]-NAD-199. Competition data were all fitted best by a two-binding site model, and agonist affinities for the higher (K-h) and lower affinity (K-1) sites were determined. 3 The ability of the agonists to activate the 5-HT1A receptor was determined using stimulation of [S-35]-GTPgammaS binding. Maximal effects of agonists (E-max) and their potencies (EC50) were determined from concentration/response curves for stimulation of [S-35]-GTPgammaS binding. 4 K-1/K-h determined from ligand binding assays correlated with the relative efficacy (relative Em) of agonists determined in [S-35]-GTPgammaS binding assays. There was also a correlation between K-1/K-h and K-1/EC50 for agonists determined from ligand binding and [S-35]-GTPgammaS binding assays. 5 Simulations of agonist binding and effect data were performed using the Ternary Complex Model in order to assess the use of K-1/K-h for predicting the relative efficacy of agonists. British Journal of Pharmacology (2003) 138, 1129-1139. doi: 10. 1038/sj.bjp.705085.

Free radicals, metals and antioxidants in oxidative stress-induced cancer

Oxygen-free radicals, more generally known as reactive oxygen species (ROS) along with reactive nitrogen species (RNS) are well recognised for playing a dual role as both deleterious and beneficial species. The "two-faced" character of ROS is substantiated by growing body of evidence that ROS within cells act as secondary messengers in intracellular signalling cascades, which induce and maintain the oncogenic phenotype of cancer cells, however, ROS can also induce cellular senescence and apoptosis and can therefore function as anti-tumourigenic species. The cumulative production of ROS/RNS through either endogenous or exogenous insults is termed oxidative stress and is common for many types of cancer cell that are linked with altered redox regulation of cellular signalling pathways. Oxidative stress induces a cellular redox imbalance which has been found to be present in various cancer cells compared with normal cells; the redox imbalance thus may be related to oncogenic stimulation. DNA mutation is a critical step in carcinogenesis and elevated levels of oxidative DNA lesions (8-OH-G) have been noted in various tumours, strongly implicating such damage in the etiology of cancer. It appears that the DNA damage is predominantly linked with the initiation process. This review examines the evidence for involvement of the oxidative stress in the carcinogenesis process. Attention is focused on structural, chemical and biochemical aspects of free radicals, the endogenous and exogenous sources of their generation, the metal (iron, copper, chromium, cobalt, vanadium, cadmium, arsenic, nickel)-mediated formation of free radicals (e.g. Fenton chemistry), the DNA damage (both mitochondrial and nuclear), the damage to lipids and proteins by free radicals, the phenomenon of oxidative stress, cancer and the redox environment of a cell, the mechanisms of carcinogenesis and the role of signalling cascades by ROS; in particular. ROS activation of AP-1 (activator protein) and NF-kappa B (nuclear factor kappa B) signal transduction pathways, which, in turn lead to the transcription of genes involved in cell growth regulatory pathways. The role of enzymatic (superoxide dismutase (Cu. Zn-SOD. Mn-SOD), catalase, glutathione peroxidase) and non-enzymatic antioxidants (Vitamin C, Vitamin E, carotenoids, thiol antioxidants (glutathione, thioredoxin and lipoic acid), flavonoids, selenium and others) in the process of careinogenesis as well as the antioxidant interactions with various regulatory factors, including Ref-1, NF-kappa B, AP-1 are also reviewed. 2006 Elsevier Ireland Ltd. All rights reserved.

Role of oxygen radicals in DNA damage and cancer incidence

The development of cancer in humans and animals is a multistep process. The complex series of cellular and molecular changes participating in cancer development are mediated by a diversity of endogenous and exogenous stimuli. One type of endogenous damage is that arising from intermediates of oxygen (dioxygen) reduction - oxygen-free radicals (OFR), which attacks not only the bases but also the deoxyribosyl backbone of DNA. Thanks to improvements in analytical techniques, a major achievement in the understanding of carcinogenesis in the past two decades has been the identification and quantification of various adducts of OFR with DNA. OFR are also known to attack other cellular components such as lipids, leaving behind reactive species that in turn can couple to DNA bases. Endogenous DNA lesions are genotoxic and induce mutations. The most extensively studied lesion is the formation of 8-OH-dG. This lesion is important because it is relatively easily formed and is mutagenic and therefore is a potential biomarker of carcinogenesis. Mutations that may arise from formation of 8-OH-dG involve GC. TA transversions. In view of these findings, OFR are considered as an important class of carcinogens. The effect of OFR is balanced by the antioxidant action of non-enzymatic antioxidants as well as antioxidant enzymes. Non-enzymatic antioxidants involve vitamin C, vitamin E, carotenoids (CAR), selenium and others. However, under certain conditions, some antioxidants can also exhibit a pro-oxidant mechanism of action. For example, beta-carotene at high concentration and with increased partial pressure of dioxygen is known to behave as a pro-oxidant. Some concerns have also been raised over the potentially deleterious transition metal ion-mediated (iron, copper) pro-oxidant effect of vitamin C. Clinical studies mapping the effect of preventive antioxidants have shown surprisingly little or no effect on cancer incidence. The epidemiological trials together with in vitro experiments suggest that the optimal approach is to reduce endogenous and exogenous sources of oxidative stress, rather than increase intake of anti-oxidants. In this review, we highlight some major achievements in the study of DNA damage caused by OFR and the role in carcinogenesis played by oxidatively damaged DNA. The protective effect of antioxidants against free radicals is also discussed.

Synthesis and crystal structure of a 3-D zinc phosphate, [C5N2H14][Zn-2(PO3(OH))(3)], containing (4.8) net sheets

A new 3-D zinc phosphate, [C5N2H14][Zn-2(PO3(OH))(3)], has been synthesised under solvothermal conditions in the presence of 1-methylpiperazine. The structure, determined by single-crystal X-ray diffraction at 293 K (RMM = 520.9, orthorhombic, space group P2(1)2(1)2(1); a = 10.0517(2) &ANGS;, b = 10.4293(2) &ANGS; and c = 14.9050(5) &ANGS;; V = 1562.52 &ANGS;(3); Z = 4; R(F) = 2.60%, wR(F) = 2.93%), consists of vertex linked ZnO4 and PO3(OH) tetrahedra assembled into (4.8) net sheets which in turn are linked through further PO3(OH) units to generate a 3-D framework. 1-Methylpiperazinium cations reside within the 3-D channel system, held in place by a strong network of hydrogen bonds. The (4.8) net sheets occur in a number of zeolite structures e.g. ABW and GIS and related zinc phosphate phases. © 2004 Academie des sciences. Published by Elsevier SAS. All rights reserved.

Synthesis and crystal structure of a 3-D zinc phosphate, [C5N2H14][Zn2(PO3(OH))3], containing (4.8) net sheets

A new 3-D zinc phosphate, [C5N2H14][Zn-2(PO3(OH))(3)], has been synthesised under solvothermal conditions in the presence of 1-methylpiperazine. The structure, determined by single-crystal X-ray diffraction at 293 K (RMM = 520.9, orthorhombic, space group P2(1)2(1)2(1); a = 10.0517(2) &ANGS;, b = 10.4293(2) &ANGS; and c = 14.9050(5) &ANGS;; V = 1562.52 &ANGS;(3); Z = 4; R(F) = 2.60%, wR(F) = 2.93%), consists of vertex linked ZnO4 and PO3(OH) tetrahedra assembled into (4.8) net sheets which in turn are linked through further PO3(OH) units to generate a 3-D framework. 1-Methylpiperazinium cations reside within the 3-D channel system, held in place by a strong network of hydrogen bonds. The (4.8) net sheets occur in a number of zeolite structures e.g. ABW and GIS and related zinc phosphate phases. © 2004 Academie des sciences. Published by Elsevier SAS. All rights reserved.

Atmospheric chemistry of C4F9OC2H5 (HFE-7200), C4F9OCH3 (HFE-7100), C3F7OCH3 (HFE-7000) and C3F7CH2OH: temperature dependence of the kinetics of their reactions with OH radicals, atmospheric lifetimes and global warming potentials

The atmospheric chemistry of several gases used in industrial applications, C4F9OC2H5 (HFE-7200), C4F9OCH3 (HFE-7100), C3F7OCH3 (HFE-7000) and C3F7CH2OH, has been studied. The discharge flow technique coupled with mass-spectrometric detection has been used to study the kinetics of their reactions with OH radicals as a function of temperature. The infrared spectra of the compounds have also been measured. The following Arrhenius expressions for the reactions were determined (in units of cm3 molecule-1 s-1): k(OH + HFE-7200) = (6.9+2.3-1.7) × 10-11 exp(-(2030 ± 190)/T); k(OH + HFE-7100) = (2.8+3.2-1.5) × 10-11 exp(-(2200 ± 490)/T); k(OH + HFE-7000) = (2.0+1.2-0.7) × 10-11 exp(-(2130 ± 290)/T); and k(OH + C3F7CH2OH) = (1.4+0.3-0.2) × 10-11 exp(-(1460 ± 120)/T). From the infrared spectra, radiative forcing efficiencies were determined and compared with earlier estimates in the literature. These were combined with the kinetic data to estimate 100-year time horizon global warming potentials relative to CO2 of 69, 337, 499 and 36 for HFE-7200, HFE-7100, HFE-7000 and CF3CF2CF2CH2OH, respectively.

A temperature-dependent relative-rate study of the OH initiated oxidation of n-butane: the kinetics of the reactions of the 1-and 2-butoxy radicals

The kinetics of the reactions of 1-and 2-butoxy radicals have been studied using a slow-flow photochemical reactor with GC-FID detection of reactants and products. Branching ratios between decomposition, CH3CH(O-.)CH2CH3 CH3CHO + C2H5, reaction (7), and reaction with oxygen, CH3CH(O-.)CH2CH3 + O-2 -> CH3C(O)C2H5 + HO2, reaction (6), for the 2-butoxy radical and between isomerization, CH3CH2CH2CH2O. -> CH2CH2CH2CH2OH, reaction (9), and reaction with oxygen, CH3CH2CH2CH2O. + O-2 -> C3H7CHO + HO2, reaction (8), for the 1-butoxy radical were measured as a function of oxygen concentration at atmospheric pressure over the temperature range 250-318 K. Evidence for the formation of a small fraction of chemically activated alkoxy radicals generated from the photolysis of alkyl nitrite precursors and from the exothermic reaction of 2-butyl peroxy radicals with NO was observed. The temperature dependence of the rate constant ratios for a thermalized system is given by k(7)/k(6) = 5.4 x 1026 exp[(-47.4 +/- 2.8 kJ mol(-1))/RT] molecule cm(-3) and k(9)/k(8) = 1.98 x 10(23) exp[(-22.6 +/- 3.9 kJ mol(-1))/RT] molecule cm(-3). The results agree well with the available experimental literature data at ambient temperature but the temperature dependence of the rate constant ratios is weaker than in current recommendations.

Influence of counter anions on the structures and magnetic properties of trinuclear Cu(II) complexes containing a mu(3)-OH core and Schiff base ligands

Four trinuclear Cu(II) complexes, [(CuL1)(3)(mu(3)-OH)](NO3)(2) (1), [(CuL2)(3)(mu(3)-OH)](I)(2)center dot H2O (2), [(CuL3)(3)(mu(3)-OH)](I)(2) (3) and [(CuL1)(3)(mu(3)-OH)][(CuI3)-I-1] (4), where HL1 (8-amino-4-methyl-5-azaoct-3-en-2-one), HL2 [7-amino-4-methyl-5-azaoct-3-en-2-one] and HL3 [7-amino-4-methyl-5-azahept-3-en-2- one] are the three tridentate Schiff bases, have been synthesized and structurally characterized by X-ray crystallography. All four complexes contain a partial cubane core, [(CuL)(3)(mu(3)-OH)](2+) in which the three [CuL] subunits are interconnected through two types of oxygen bridges afforded by the oxygen atoms of the ligands and the central OH- group. The copper(II) ions are in a distorted square-pyramidal environment. The equatorial plane consists of the bridging oxygen of the central OH- group together with three atoms (N, N, O) from the Schiff base. The oxygen atom of the Schiff base also coordinates to the axial position of Cu(II) of another subunit to form the cyclic trimer. Magnetic susceptibilities have been determined for these complexes over the temperature range of 2-300 K. The isotropic Hamiltonian, H = -J(12)S(1)S(2) - J(13)S(1)S(3) - J(23)S(2)S(3) has been used to interpret the magnetic data. The best fit parameters obtained are: J = - 54.98 cm(-1) g = 2.24 for 1; J = - 56.66 cm(-1), g = 2.19 for 2; J = -44.39 cm(-1), g = 2.16 for 3; J = - 89.92 cm(-1), g = 2.25 for 4. The EPR data at low temperature indicate that the phenomenon of spin frustration occurs for complexes 1-3. (c) 2007 Elsevier B.V. All rights reserved.

Gas-phase rate coefficients for the reactions of NO3, OH and O-3 with alpha,beta-unsaturated esters and ketones: structure-activity relations (SARs)

Gas-phase rate coefficients for the atmospherically important reactions of NO3, OH and O-3 are predicted for 55 alpha,beta-unsaturated esters and ketones. The rate coefficients were calculated using a correlation described previously [Pfrang, C., King, M.D., C. E. Canosa-Mas, C.E., Wayne, R.P., 2006. Atmospheric Environment 40, 1170-1179]. These rate coefficients were used to extend structure-activity relations for predicting the rate coefficients for the reactions of NO3, OH or O-3 with alkenes to include alpha,beta-unsaturated esters and ketones. Conjugation of an alkene with an alpha,beta-keto or alpha,beta-ester group will reduce the value of a rate coefficient by a factor of similar to 110, similar to 2.5 and similar to 12 for reaction with NO3, OH or O-3, respectively. The actual identity of the alkyl group, R, in -C(O)R or -C(O)OR has only a small influence. An assessment of the reliability of the SAR is given that demonstrates that it is useful for reactions involving NO3 and OH, but less valuable for those of O-3 or peroxy nitrate esters. (c) 2006 Elsevier Ltd. All rights reserved.

Coordination modes of 3-aminosalicylic and 3-hydroxyanthranilic acids in palladium(II), platinum(II) and rhenium(V) complexes. The crystal structure of cis-[Pt(HsalNH)(PPh3)(2)] (.) 0.25C(2)H(5)OH

New Pd(II), Pt(II) and Re(V) complexes of 3-aminosalicylic acid (H(2)salNH(2)) and 3-hydroxyantranilic acid (HantOH) have been prepared, cis-[Pt (HsalNH)(PPh3)(2)] center dot 0.25C(2)H(5)OH (1), trans-[PdCl(salNH(2))(PPh3)(2)](2), trans-[ReOI2(HsalNH(2))(PPh3)] center dot (CH3)(2)CO (3), cis-[Pt(HantO)(PPh3)(2)] (4), trans-[PdCl(antOH)(PPh3)(2)] center dot 4H(2)O (5), [PdCl(antOH)(bipy)] center dot C2H5OH (6), [PdCl2(HantOH)(2)] (7) and trans-[ReOI(HantO)(PPh3)(2)] center dot (CH3)(2)CO (8). The crystal structure of complex I was determined showing chelation of HsalNH(2-) through the adjacent nitrogen and oxygen atoms of the amino and phenolate groups. Infrared and H-1 NMR spectroscopic data for the complexes are presented. (c) 2005 Elsevier Ltd. All rights reserved.

Trinuclear cu(ll) complexes containing peripheral ketonic oxygen bridges and a mu(3)-OH core: Syntheses, crystal structures, spectroscopic and magnetic properties

Four new trinuclear copper(II) complexes, [(CuL1)(3)(mu(3)-OH)](ClO4)(2)center dot H2O (1), [(CuL2)(3)(mu(3)-OH)](CIO4)(2) (2), [(CuL3)(3)-(mu(3)-OH)](ClO4)(4)center dot H2O (3), and [(CuL4)(3)(mu(3)-OH)](ClO4)(2)center dot H2O (4), where HL1 = 8-amino-4,7,7-trimethyl-5-azaoct-3-en-2-one, HL2 = 7-amino-4-methyl-5-azaoct-3-en-2-one, HL3 = 7(ethylamino)-4-methyl-5-azahept-3-en-2-one, and HL4 = 4-methyl-7-(methylamino)-5-azahept-3-en-2-one, have been derived from the four tridentate Schiff bases (HL1, HL2, HL3, and HL4) and structurally characterized by X-ray crystallography. For all compounds, the cationic part is trinuclear with a CU3OH core held by three carbonyl oxygen bridges between each pair of copper(II) atoms. The copper atoms are five-coordinate with a distorted square-pyramidal geometry; the equatorial plane consists of the bridging oxygen atom of the central OH group together with three atoms (N, N, O) from one ligand whereas an oxygen atom of a second ligand occupies the axial position. Magnetic measurements have been performed in the 2-300 K temperature range. The experimental data could be satisfactorily reproduced by using an isotropic exchange model, H = -J(S1S2+S2S3+S1S3) yielding as best-fit parameters: J = -66.7 and g = 2.19 for 1, J = -36.6 and g = 2.20 for 2, J = -24.5 and g = 2.20 for 3, and J = -14.9 and g = 2.05 for 4. EPR spectra at low temperature show the existence of spin frustration in complexes 3 and 4, but it has not been possible to carry out calculations of the antisymmetric exchange parameter, G, from magnetic data. In frozen methanolic solution, at 4 K, hyperfine splitting in all complexes and spin frustration in complex 4 seem to be confirmed. ((c) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

Kinetic studies of reactions of the nitrate radical (NO3) with peroxy radicals (RO2): an indirect source of OH at night?

A discharge-flow system, coupled to cavity-enhanced absorption spectroscopy (CEAS) detection systems for NO3 at lambda = 662 nm and NO2 at lambda = 404 nm, was used to investigate the kinetics of the reactions of NO3 with eight peroxy radicals at P similar to 5 Torr and T similar to 295 K. Values of the rate constants obtained were (k/10(-12) cm(3) molecule(-1) s(-1)): CH3O2 (1.1 +/- 0.5), C2H5O2 (2.3 +/- 0.7), CH2FO2 (1.4 +/- 0.9), CH2ClO2 (3.8(-2.6)(+1.4)), c-C5H9O2 (1.2(-0.5)(+1.1)), c-C6H11O2 (1.9 +/- 0.7), CF3O2 (0.62 +/- 0.17) and CF3CFO2CF3 (0.24 +/- 0.13). We explore possible relationships between k and the orbital energies of the reactants. We also provide a brief discussion of the potential impact of the reactions of NO3 with RO2 on the chemistry of the night-time atmosphere.