Abstract:Recommendations are made for standard potentials involving select inorganic radicals in aqueous solution at 25 °C. These recommendations are based on a critical and thorough literature review and also by performing derivations from various literature reports. The recommended data are summarized in tables of standard potentials, Gibbs energies of formation, radical pK a 's, and hemicolligation equilibrium constants. In all cases, current best estimates of the uncertainties are provided. An extensive set of Data Sheets is appended that provide original literature references, summarize the experimental results, and describe the decisions and procedures leading to each of the recommendations.

Radiation chemical methods were used to investigate the reactions of glycine anions, H2NCH2CO2 - (Gly-), with •OH, (CH3)2C•OH, and •CH3 radicals. A major and most significant product from all of these processes is CO2. Pulse-radiolysis revealed that the initial step in the •OH-induced mechanism is oxidation of the amino group, producing +H2N•-CH2-CO2 - and HN•-CH2-CO2 - with yields of 63% and 37%, respectively. The amino radical cation, +H2N•-CH2-CO2 -, suffers fast (≤100 ns) fragmentation into CO2 + •CH2NH2. The other primary radical, HN•-CH2-CO2 -, can also be converted into the decarboxylating +H2N•-CH2-CO2 - by reaction with proton donors such as phosphate (H2PO4 -/k = 7.4 × 107 M-1 s-1, and HPO4 2-/k = 2.5 × 105 M-1 s-1) or the glycine zwitterion, Gly± (k = 3.9 × 105 M-1 s-1), but only on a much longer (typically μs to ms) time scale (k ≈ 4 × 105 M-1 s-1). Competitively, the HN•-CH2-CO2 - transforms into a carbon-centered radical H2N-C•H-CO2 - either by an intramolecular 1,2-H-atom shift (k = (1.2 ± 1.0) × 103 s-1) or by bimolecular reaction with Gly- (k = (3.0 ± 0.2) × 104 M-1 s-1). Both C-centered radicals, H2N-C•H-CO2 - and •CH2NH2, are reductants as verified through their reactions with Fe(CN)6 3- and methyl viologen (MV2+) in pulse-radiolysis experiments (k ≈ 4 × 109 M-1 s-1). The eventual complete transformation of all primary radicals into H2N-C•H-CO2 - and •CH2NH2 was further substantiated by γ-radiolytic reduction of Fe(CN)6 3-. In the presence of suitable electron donors, the HN•-CH2-CO2 - radical acts as an oxidant. This was demonstrated through its reaction with hydroquinone (k = (7.4 ± 0.5) × 107 M-1 s-1). Although the C-centered H2N-C•H-CO2 - radical is not generated in a direct H-atom abstraction by •OH, this radical appears to be the exclusive product in the reaction of Gly- with (CH3)2C•OH, •CH2NH2, and •CH3 (k ≈ 102 M-1 s-1). A most significant finding is that H2N-C•H-CO2 - can be converted into the decarboxylating N-centered radical cation +H2N•-CH2-CO2 - by reaction with proton donors such as Gly± (k ≈ 3 × 103 M-1 s-1) or phosphate and thus also becomes a source of CO2. The •CH2NH2-induced route establishes, in fact, a chain mechanism which could be proven through dose rate effect experiments and suppression of the chain upon addition of Fe(CN)6 3- or MV2+ as a scavenger for the reducing precursor radicals. The possible initiation of amino acid decarboxylation by C-centered radicals and the assistance of proton donors at various stages within the overall mechanism are considered to be of general significance and interest in chemical and biological systems.

No abstract

Human genetic studies have implicated the voltage-gated sodium channel NaV1.7 as a therapeutic target for the treatment of pain. A novel peptide, μ-theraphotoxin-Pn3a, isolated from venom of the tarantula Pamphobeteus nigricolor, potently inhibits NaV1.7 (IC50 0.9 nM) with at least 40–1000-fold selectivity over all other NaV subtypes. Despite on-target activity in small-diameter dorsal root ganglia, spinal slices, and in a mouse model of pain induced by NaV1.7 activation, Pn3a alone displayed no analgesic activity in formalin-, carrageenan- or FCA-induced pain in rodents when administered systemically. A broad lack of analgesic activity was also found for the selective NaV1.7 inhibitors PF-04856264 and phlotoxin 1. However, when administered with subtherapeutic doses of opioids or the enkephalinase inhibitor thiorphan, these subtype-selective NaV1.7 inhibitors produced profound analgesia. Our results suggest that in these inflammatory models, acute administration of peripherally restricted NaV1.7 inhibitors can only produce analgesia when administered in combination with an opioid.