N-(4-Bromo-2,5-Dimethoxyphenethyl)-6-(4-Phenylbutoxy)Hexan-1-Amine (XOB): A Novel Phenylalkylamine Antagonist of Serotonin 2A Receptors and Voltage-Gated Sodium Channels.

Bipolar disorder impacts millions of patients in the United States but the mechanistic understanding of its pathophysiology and therapeutics is incomplete. Atypical antipsychotic serotonin2A (5-HT2A) receptor antagonists, such as quetiapine and olanzapine, and mood-stabilizing voltage-gated sodium channel (VGSC) blockers, such as lamotrigine, carbamazepine, and valproate, show therapeutic synergy and are often prescribed in combination for the treatment of bipolar disorder. Combination therapy is a complex task for clinicians and patients, often resulting in unexpected difficulties with dosing, drug tolerances, and decreased patient compliance. Thus, an unmet need for bipolar disorder treatment is to develop a therapeutic agent that targets both 5-HT2A receptors and VGSCs. Toward this goal, we developed a novel small molecule that simultaneously antagonizes 5-HT2A receptors and blocks sodium current. The new compound, N-(4-bromo-2,5-dimethoxyphenethyl)-6-(4-phenylbutoxy)hexan-1-amine (XOB) antagonizes 5-HT-stimulated, Gq-mediated, calcium flux at 5-HT2A receptors at low micromolar concentrations while displaying negligible affinity and activity at 5-HT1A, 5-HT2B, and 5-HT2C receptors. At similar concentrations, XOB administration inhibits sodium current in heterologous cells and results in reduced action potential (AP) firing and VGSC-related AP properties in mouse prefrontal cortex layer V pyramidal neurons. Thus, XOB represents a new, proof-of-principle tool that can be used for future preclinical investigations and therapeutic development. This polypharmacology approach of developing a single molecule to act upon two targets, which are currently independently targeted by combination therapies, may lead to safer alternatives for the treatment of psychiatric disorders that are increasingly being found to benefit from the simultaneous targeting of multiple receptors. SIGNIFICANCE STATEMENT: The authors synthesized a novel small molecule (XOB) that simultaneously antagonizes two key therapeutic targets of bipolar disorder, 5-HT2A receptors and voltage-gated sodium channels, in heterologous cells, and inhibits the intrinsic excitability of mouse prefrontal cortex layer V pyramidal neurons in brain slices. XOB represents a valuable new proof-of-principle tool for future preclinical investigations and provides a novel molecular approach to the pharmacological treatment of complex neuropsychiatric disease, which often requires a combination of therapeutics for sufficient patient benefit.

Orally available Mn porphyrins with superoxide dismutase and catalase activities.

Superoxide dismutase/catalase mimetics, such as salen Mn complexes and certain metalloporphyrins, catalytically neutralize reactive oxygen and nitrogen species, which have been implicated in the pathogenesis of many serious diseases. Both classes of mimetic are protective in animal models of oxidative stress. However, only AEOL11207 and EUK-418, two uncharged Mn porphyrins, have been shown to be orally bioavailable. In this study, EUK-418 and several new analogs (the EUK-400 series) were synthesized and shown to exhibit superoxide dismutase, catalase, and peroxidase activities in vitro. Some also protected PC12 cells against staurosporine-induced cell death. All EUK-400 compounds were stable in simulated gastric fluid, and most were substantially more lipophilic than the salen Mn complexes EUK-189 and EUK-207, which lack oral activity. Pharmacokinetics studies demonstrate the presence of all EUK-400 series compounds in the plasma of rats after oral administration. These EUK-400 series compounds are potential oral therapeutic agents for cellular damage caused by oxidative stress.

Effect of the introduction of a lumbar-puncture sticker and teaching manikin on junior staff documentation and performance of paediatric lumbar punctures.

BACKGROUND: Performing a lumbar puncture in an unwell child can cause anxiety in both the parent and the junior doctor. There is increasing evidence of post-lumbar-puncture complications in this age group. AIMS: To improve the documentation, consent for and technical performance of paediatric lumbar punctures to 100% of the required standard within 3 months. SETTING: The paediatric emergency department of a the Royal North Shore Hospital (University of Sydney, Sydney, Australia). PARTICIPANTS: Paediatric emergency staff, including residents, registrars and consultants. METHODS: Medical records of 40 consecutive children who had undergone a lumbar puncture in the 6 months before the introduction of the lumbar-puncture proforma were reviewed. After introduction of the proforma, the records of 25 consecutive patients were reviewed to assess changes in the outcome measures. Before introduction of the proforma, junior medical staff were instructed in the procedure using specialised lumbar puncture manikins (Baby Stap; Laerdel, USA). RESULTS: Before introduction of the proforma, the median number of documented indicators was 4, out of a maximum of 12. There was almost no documentation of parental consent, patient complications and analgesia. Introduction of the proforma resulted in a highly marked increase to a median of 12 documented indicators per patient (p<0.01, 95% confidence interval 6 to 8). CONCLUSIONS: The introduction of a lumbar-puncture proforma and formal teaching sessions using a paediatric manikin led to a marked improvement in the documentation of paediatric lumbar-punctures. Lumbar-punctures can be performed only by accredited medical officers who have achieved competency on the lumbar-puncture teaching manikin.

Synthesis and characterization of a discotic uranium-containing liquid crystal.

The synthesis of several UO(2)-alaskaphyrin derivatives functionalized with aliphatic chains is described. These compounds are found to be liquid-crystalline and form columnar mesophases, as judged from polarizing optical microscopy studies, and represent the first uranium-containing discotic mesogens.