Pharmacological Investigations of N-Substituent Variation in Morphine and Oxymorphone: Opioid Receptor Binding, Signaling and Antinociceptive Activity

Morphine and structurally related derivatives are highly effective analgesics, and the mainstay in the medical management of moderate to severe pain. Pharmacological actions of opioid analgesics are primarily mediated through agonism at the mopioid peptide (MOP) receptor, a G protein-coupled receptor. Position 17 in morphine has been one of the most manipulated sites on the scaffold and intensive research has focused on replacements of the 17-methyl group with other substituents. Structural variations at the N-17 of the morphinan skeleton led to a diversity of molecules appraised as valuable and potential therapeutics and important research probes. Discovery of therapeutically useful morphine-like drugs has also targeted the C-6 hydroxyl group, with oxymorphone as one of the clinically relevant opioid analgesics, where a carbonyl instead of a hydroxyl group is present at position 6. Herein, we describe the effect of N-substituent variation in morphine and oxymorphone on in vitro and in vivo biological properties and the emerging structure-activity relationships. We show that the presence of a N-phenethyl group in position 17 is highly favorable in terms of improved affinity and selectivity at the MOP receptor, potent agonism and antinociceptive efficacy. The N-phenethyl derivatives of morphine and oxymorphone were very potent in stimulating G protein coupling and intracellular calcium release through the MOP receptor. In vivo, they were highly effective against acute thermal nociception in mice with marked increased antinociceptive potency compared to the lead molecules. It was also demonstrated that a carbonyl group at position 6 is preferable to a hydroxyl function in these N-phenethyl derivatives, enhancing MOP receptor affinity and agonist potency in vitro and in vivo. These results expand the understanding of the impact of different moieties at the morphinan nitrogen on ligand-receptor interaction, molecular mode of action and signaling, and may be instrumental to the development of new opioid therapeutics

Non-invasive single bunch monitoring for ps pulse radiolysis

A single-shot electro-optic (EO) diagnostic has been installed on the ELYSE photocathode RF gun accelerator to monitor the electron bunch at the place and under the conditions of the ps pulse radiolysis experiments. The EO signal is due to the coulombic field of the electron bunch and to a contribution of a free-space THz radiation generated by the same electron pulse. This signal is recorded shot-to-shot at the repetition rate of the accelerator. The jitter of the arrival time of the electron bunch is characterized for the first time with a non-invasive method and is confirmed to be around 1 ps. © 2009 Elsevier Ltd. All rights reserved

Non-invasive single bunch monitoring for ps pulse radiolysis

A single-shot electro-optic (EO) diagnostic has been installed on the ELYSE photocathode RF gun accelerator to monitor the electron bunch at the place and under the conditions of the ps pulse radiolysis experiments. The EO signal is due to the coulombic field of the electron bunch and to a contribution of a free-space THz radiation generated by the same electron pulse. This signal is recorded shot-to-shot at the repetition rate of the accelerator. The jitter of the arrival time of the electron bunch is characterized for the first time with a non-invasive method and is confirmed to be around 1 ps. © 2009 Elsevier Ltd. All rights reserved

Electron Transfer at Oxide/Water Interfaces Induced by Ionizing Radiation

The electron transfer from oxide into water is studied in nanoparticle suspensions of various oxides (SiO₂, ZnO, Al₂O₃, Nd₂O₃, Sm₂O₃, and Er₂O₃) by means of pulse and γ radiolysis. The time-resolved and steady-state investigations of the present study demonstrate independently that whatever the band gap and the electron affinity of the oxide, the electron transfer always takes place in these nanometric systems: Irradiation generates hot electrons which have enough energy to cross the semiconductor–liquid interface. Moreover, picosecond measurements evidence that the spectrum of the solvated electron is the same as in water. Lastly, the decay of the solvated electron is similar on the picosecond to nanosecond time scale in water and in these suspensions, but it is clearly different on the nanosecond to microsecond time scale