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The low effectiveness of morphine and related mu opioid analgesics for the treatment of chronic inflammatory pain is a result of opioid-induced release of proinflammatory cytokines and glutamate that lower the pain threshold. In this regard, the use of opioids with metabotropic glutamate-5 receptor (mGluR5) antagonist has been reported to increase the efficacy of morphine and prevent the establishment of adverse effects during chronic use. Given the presence of opioid receptors (MORs) and mGluR5 in glia and neurons, together with reports that suggest coexpressed MOR/mGluR5 receptors in cultured cells associate as a heteromer, the possibility that such a heteromer could be a target in vivo was addressed by the design and synthesis of a series of bivalent ligands that contain mu opioid agonist and mGluR5 antagonist pharmacophores linked through spacers of varying length (10-24 atoms). The series was evaluated for antinociception using the tail-flick and von Frey assays in mice pretreated with lipopolysaccharide (LPS) or in mice with bone cancer. In LPS-pretreated mice, MMG22 (4c, 22-atom spacer) was the most potent member of the series (intrathecal ED50 ~9 fmol per mouse), whereas in untreated mice its ED50 was more than three orders of magnitude higher. As members of the series with shorter or longer spacers have ⩾500-fold higher ED50s in LPS-treated mice, the exceptional potency of MMG22 may be a result of the optimal bridging of protomers in a putative MOR-mGluR5 heteromer. The finding that MMG22 possesses a >106 therapeutic ratio suggests that it may be an excellent candidate for treatment of chronic, intractable pain via spinal administration. [ABSTRACT FROM AUTHOR]

MDAN-21, 7'-{2-[(7-{2-[({(5α,6α)-4,5-Epoxy-3,14-dihydroxy-17-methylmorphin-6-yl}-aminocarbonyl)metoxy]-acetylamino} -heptylaminocarbonyl)-methoxy]-acetylamino}-naltrindole, a bivalent opioid ligand containing a mu-opioid receptor agonist (derived from oxymorphone) linked to the delta-opioid receptor antagonist (related to naltrindole) by a spacer of 21 atoms, was reported to have potent analgesic properties in mice. Tolerance, physical dependence, and conditioned place preference were not evident in that species. The finding that bivalent ligands in this series, with spacers 19 atoms or greater, were devoid of tolerance and dependence led to the proposal that MDAN-21 targets heteromeric mu-delta-opioid receptors. The present study focused on its effects in nonhuman primates (Macaca mulatta), a species with a physiology and behavioral repertoire not unlike humans. With regard to opioids, this species usually better predicts clinical outcomes. MDAN-21 substituted for morphine in morphinedependent monkeys in the remarkably low dose range 0.006-0.032 mg/kg, subcutaneously. Although MDAN-21 failed to produce reliable thermal analgesia in the dose range 0.0032-0.032 mg/kg, intramuscularly, it was active in the same dose range and by the same route of administration, in the capsaicin-induced thermal allodynia assay. The results suggest that MDAN-21 may be useful in the treatment of opioid dependence and allodynia. The data provide additional evidence that opioid withdrawal is associated with sensitized pain. [ABSTRACT FROM AUTHOR]

We have synthesized the three Schiff-base ligands H2L1-H2L3 and their CoII, FeIII and RuIII metal complexes. All compounds have been characterized by analytical and spectroscopic methods. Oxidation of cyclohexane has been done by the metal complexes in CH3CN using H2O2 and/or t-butylhydroperoxide (TBHP) as a co-catalyst. The keto-enol tautomeric forms of the ligands have been studied in polar and non-polar organic solvents. Electrochemical properties of the complexes have been studied at different scan rates. Thermal studies were carried out for the compounds. The ligands H2L1-H2L3 were mutagenic on Salmonella Typhimurium TA 98 strain in the presence and/or absence of S9 mix. While the ligands H2L1 and H2L2 showed mutagenic activity on the strain TA 100 with and without S9 mix, the ligand H2L3 was not mutagenic for TA 100. Antimicrobial activity studies of the compounds have also been carried out. [ABSTRACT FROM AUTHOR]

Acylation of silylenol ethers 1 and 9 yield with 2-alkoxy-2-alkyl(or aryl)-1,3-dioxolanes 5 in a simple way by zinc dichloride-diethyl ether-catalysis regioselectively the α- and γ-protected dicarbonyl derivatives 6, 7, and 10. The enhanced reactivity of the cyclic orthoesters 5 in this reaction is discussed in comparison with acyclic reagents. The yield is influenced by steric effects at the reaction center. [ABSTRACT FROM AUTHOR]

Some new experimental results are described on the acid catalysed reaction of the 4-Pyrazoline-3-on ( 1a) with aromatic aldehydes leading to the cationic derivatives 4 and 5. 4-Pyrazoline-3-on-lithium ( 1b), synthesised for the first time, gives in good yield with 4-dimethylaminobenzaldehyde under mild condition the cyanine 2b and with benzophenone the pyrazolyl-diphenylmethane dye 8. [ABSTRACT FROM AUTHOR]

The 4-pyrazoline-3-one 1 reacts with 4-dimethylaminobenzaldehyde to yield the stable asymmetric cyanine dye 2b which reacts with 1 to give the colorless (aryl) (dipyrazolyl) methane 3b. Using aldehydes with less cationstabilizing groups the polymethines 2 are not isolated but only the methanes 3. The structures of 2b and 3 are discussed by H,C and Hetero NMR spectra. [ABSTRACT FROM AUTHOR]