TLR9 is a key determinant of the innate immune responses in both infectious and sterile injury. Specific antagonism of TLR9 is of great clinical interest to reduce tissue damage in a wide range of pathologies, and has been approached by modification of nucleic acids, the recognized ligand for TLR9. Such oligonucleotide-derived pharmacotherapeutics have limitations in specificity for nucleic acid receptors, significant potential for immunologic recognition with generation of innate and adaptive immune responses, and limited bioavailability. We have identified enantiomeric analogues of traditional (−)-morphinans as having TLR9 antagonist properties on reporter cell lines. One of these analogues (COV08-0064) is demonstrated to be a novel small molecule antagonist of TLR9 with greater specificity for TLR9 than oligo based antagonists. COV08-0064 has wide bioavailability, including the subcutaneous and per oral route. It specifically inhibits the action of TLR9 antagonists on reporter cells lines and the production of cytokines by TLR9 agonists from primary cells. It also has efficacy in limiting TLR9 mediated sterile inflammation in in vivo models of acute liver injury and acute pancreatitis. The identification of a morphinan based novel small molecule structure with TLR9 antagonism is a significant step in expanding therapeutic strategies in the field of sterile inflammatory injury.

The effects of applied voltages and reaction times on negative ion chemical ionization in the quadrupole ion trap are investigated. Mass-selected ejection of undesired reagent ions and selective mass storage of only negative ions are required for practical negative ion chemical ionization. This is achieved by application of rf and dc voltages to the ring electrode to control the mass-to-charge ratios one polarity) of ions stored, as well as by application of a supplemental rf voltage applied across the endcap electrodes to selectively eject ions of a particular mass-to-charge ratio. Even with careful control of these parameters, negative chemical ionization is not as sensitive as electron ionization and positive chemical ionization because of the lack of thermal electrons in the ion trap. Mass selection of the hydroxide anion as a reagent ion and exclusion of all positive ions provide [M - H](-) ions with little or no fragmentation for a wide variety of compounds.

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Key indicators: single-crystal X-ray study; T = 100 K; mean (C-C) = 0.002 Å; R factor = 0.027; wR factor = 0.069; data-to-parameter ratio = 15.1.In the crystal structure of the title compound, C 28 H 36 O 4 S, the p-tolyl ring is inclined at 35.8 to the aromatic ring. The cyclohexene ring adopts a boat conformation and the heterocyclic ring is in a slightly distorted screw boat conformation. Related literatureFor the physiological actions of tetrahydrocannabinol (Á 9 -THC), the most psychologically active constituent of Cannabis sativa, see: Mechoulam & Gaoni (1967). For the synthesis of