William M. Willingham

Copper complexes of non-steroidal antiinflammatory agents: Analgesic activity and possible opioid receptor activation

Cu(II)2(acetylsalicylate)4, Cu(II)(anthranilate)2, Cu(II)2[1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3-indolylacetate]4, Cu(II)(3,5-diisopropylsalicylate)2, Cu(II)(salicylate)2, Cu(II)2{2-[3-(trifluoromethyl)-phenyl]aminonicotinate}4, Cu(II)(l-alaninate)2, Cu(II)(l-cystinate)2, and Cu(II)(glycinate)2 were generally found to be more effective analgesics than their parent ligands, Cu(II)(chloride)2, and Cu(II)2(acetate)4 in the Writhing Mouse and Adjuvant Arthritic Rat pain models following subcutaneous and oral administration. Comparison of the time course of analgesia for salicylic acid and Cu(II)(salicylate)2 in the adjuvant arthritis pain model revealed that this complex had more sustained activity in addition to being more potent than salicylic acid. Cu(II)2(indomethacin)4 was also found to be as effective as morphine in both pain models. These data and pertinent literature are discussed in support of the hypothesis that copper complexes activate copper-dependent opioid receptors.

Copper-, iron-, manganese- and zinc-3,5-diisopropylsalicylate complexes increase survival of gamma-irradiated mice

Eighty μmol/kg of copper(II)2(3,5-diisopropylsalicylate)4(H2O)2 [Cu(II)2(3,5-DIPS)4] given subcutaneously (sc) to female mice 24 h before lethal (LD10030) irradiation was found to allow 58% survival. Subsequent studies using LD5030 irradiations revealed that 80 or 92% survival was obtained in female or male mice, respectively, when 20 μmol/kg was given 3 h before irradiation; 88–92% survival was achieved in female mice treated with 2.5, 5, or 10 μmol/kg 3 h after irradiation; and 75 or 95% of the male mice survived when they had been given 50 μmol/kg orally 24 or 4 h, respectively, before irradiation. Using LD5030 irradiations it was also found that administration of 280 μmol of Fe(III)-(3,5-DIPS)3(H2O)/kg led to 84% survival in male mice; 80 μmol of Mn(II)-(3,5-DIPS)2(H2O)/kg allowed 96 or 100% survival in male or female mice, respectively; and 60 μmol Zn(II)-(3,5-DIPS)2/kg achieved 95% survival in male mice. In addition, all of these complexes were found to have anti-convulsant activities suggesting possible protection against radiation-induced seizures. It is concluded that these essential metalloelement complexes have radiation-protection and radiation-recovery activities and that their use represents a physiological approach to preventing or perhaps predominantly facilitating recovery from radiation injury.

Copper(II)ethylenediaminetetraacetate does disproportionate superoxide

The superoxide dismutase (SOD) mimetic reactivity of Cu(II)EDTA was studied in the pH range of 6.0 to 8.0. Cu(II)EDTA disproportionated superoxide without inhibiting superoxide production by xanthine oxidase, as a result of bonding sites becoming available on the copper complex with increasing acidity. This disproportionation by Cu(II)EDTA is offered as evidence that the addition of EDTA to biological preparations for the purpose of complexing copper and thereby inhibiting copper-dependent superoxide disproportionation and promoting superoxide-dependent reactions is not a valid practice.

Copper Complexes Have Potent Analgesic Activity and They May Activate Opioid Receptors

\text{Manganese}({\rm III})_{2}({\rm II})(\mu _{3}\text{-}{\rm O})(\mu \text{-}3,5\text{-diisopropylsalicylate})_{6}

Comparison of the radiorecovery activity of copper(II)2(3,5-diisopropylsalicylate)4 and copper(II) (chloride)2

[{\rm Mn}_{3}({\rm O})(3,5\text{-}{\rm DIPS})_{6}]

Structure of trans-aqua-bis(pyridine)dibenzoatocopper(II)

was used to treat female C57BL/6 mice irradiated with

pH-Dependent Superoxide Dismutase-Mimetic Reactivity of Copper(II)Ethylenediaminetetraacetate

{\rm LD}_{50/30}

Radioprotectant Activity of 5-Diethylsulfonamoylsalicylatocopper(II) in Gamma Irradiated Mice

doses of ? rays and examine the possibility that treatment after irradiation increases survival. Female C57BL/6 mice were treated with 0, 10, 20, or 40 ?mol