NMR spectral analysis of second-order 19F-19F, 19F-1H and 13C-19F coupling constants in pentafluorobenzene and tetrafluoro-4-(morpholino)pyridine using ANATOLIA

A new and simple to use line-shape analysis method ANATOLIA (ANAlysis of TOtal LIneshApe) optimised all and 19F19F and 19F1H coupling constants in pentafluorobenzene (AA’BB’C’H) within 10 seconds. This free and open-source NMR analysis method, which works within the Bruker Topspin-4 software and can import Bruker/JEOL/Varian data, was able to accommodate grossly inaccurate input coupling constants to provide an accurate result even for the second-order interactions 4 JAA’ and 4 JBB’. The 13C spectrum and the 19F13C-satellites share the same coupling values, but required manual intervention to achieve an acceptable fit, especially for the 19FBB’- 13C-satellites which are deceptively simple but have significant second-order effects and display Δδ 19FB – 19FB’ of ~100 Hz. A real-world analysis of a new compound, that has potential anti-cancer drug activity, tetrafluoro-4-(morpholino)pyridine molecule, is shown for the first time. The 19F spectrum consists of a spin-system of 8 coupling nuclei (AA’BB’-H4) which was analysed within 20 seconds. The 13C satellites in the 19F spectrum consist of 9-spins (AA’BB’- 13C-H4) and the carbon spectrum shows a series of 13C isotopomer multiplets consisting of 5 coupling nuclei ( 13C-AA’BB’) was optimised in less than a minute using a laptop computer. Ab initio structure optimisations were carried out using B3LYP/6-31G*, and chemical shifts and coupling constants were calculated with the basis-set B3LYP/6-311++G**. Fluorine and carbon chemical shifts were in reasonable agreement with experimental values, and n JFF and 2-4 JCF couplings were close to the experimental values, such that these were reasonable starting values for the ANATOLIA optimisation

Data_Sheet_1_Safety, tolerability, pharmacodynamic and wellbeing effects of SPL026 (dimethyltryptamine fumarate) in healthy participants: a randomized, placebo-controlled phase 1 trial.docx

BackgroundDue to their potential impact on mood and wellbeing there has been increasing interest in the potential of serotonergic psychedelics such as N,N-dimethyltryptamine (DMT) in the treatment of major depressive disorder (MDD).AimThe aim of Part A of this study was to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamic (PD) profile of escalating doses of SPL026 (DMT fumarate) in psychedelic-naïve healthy participants to determine a dose for administration to patients with MDD in the subsequent Phase 2a part of the trial (Part B: not presented in this manuscript).MethodsIn the Phase 1, randomized, double-blind, placebo-controlled, parallel-group, single dose-escalation trial, psychedelic-naïve participants were randomized to placebo (n = 8) or four different escalating doses [9, 12, 17 and 21.5 mg intravenously (IV)] of SPL026 (n = 6 for each dose) together with psychological support from 2 therapy team members. PK and acute (immediately following dosing experience) psychometric measures [including mystical experience questionnaire (MEQ), ego dissolution inventory (EDI), and intensity rating visual analogue scale (IRVAS)] were determined. Additional endpoints were measured as longer-term change from baseline to days 8, 15, 30 and 90. These measures included the Warwick and Edinburgh mental wellbeing scale and Spielberger’s state-trait anxiety inventory.ResultsSPL026 was well tolerated, with an acceptable safety profile, with no serious adverse events. There was some evidence of a correlation between maximum plasma concentration and increased IRVAS, MEQ, and EDI scores. These trends are likely to require confirmation in a larger sample size. Using the analysis of the safety, tolerability, PD, PK results, doses of 21.5 mg SPL026 were the most likely to provide an intense, tolerated experience.ConclusionBased on the data obtained from this part of the trial, a dose of 21.5 mg SPL026 given as a 2-phase IV infusion over 10 min (6 mg/5 min and 15.5 mg/5 min) was selected as the dose to be taken into patients in Part B (to be presented in a future manuscript).Clinical trial registration:www.clinicaltrials.gov, identifier NCT04673383; https://www.clinicaltrialsregister.eu, identifier 2020-000251-13; https://www.isrctn.com/, identifier ISRCTN63465876.</p