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Ketones are converted with very high stereocontrol into functionalised medium rings incorporating a β-hydroxy ketone assembly via a ring-expansion mediated by tin(IV) chloride at low temperatures; either the threo or the erythro aldol products can be obtained. An asymmetric epoxidation permitted a subsequent highly enantiocontrolled semi-pinacol rearrangement. [Copyright &y& Elsevier]

Abstract: The hypothalamic peptides orexin-A and orexin-B are potent agonists of two G-protein coupled receptors, namely the OX1 and the OX2 receptor. These receptors are widely distributed, though differentially, in the rat brain. In particular, the OX1 receptor is highly expressed throughout the hypothalamus, whilst the OX2 receptor is mainly located in the ventral posterior nucleus. A large body of compelling evidence, both pre-clinical and clinical, suggests that the orexin system is profoundly implicated in sleep disorders. In particular, modulation of the orexin receptors activation by appropriate antagonists was proven to be an efficacious strategy for the treatment of insomnia in man. A novel, drug-like bis-amido piperidine derivative was identified as potent dual OX1 and OX2 receptor antagonists, highly effective in a pre-clinical model of sleep. [Copyright &y& Elsevier]

Abstract: Inhibitors of the glycine transporter GlyT-1 are being developed as potential treatments for schizophrenia. Here we report on the use of two novel radioligands, [3H]-SB-733993 and [3H]-GSK931145, for the characterisation of GlyT-1 in both cells and native tissue. Binding was evaluated in membranes either from HEK293 cells expressing recombinant human GlyT-1 (hGlyT-1) or from rat cerebral cortex. Specific binding of both [3H]-SB-733993 and [3H]-GSK931145 to hGlyT-1 HEK293 cell membranes and rat cerebral cortex membranes was saturable and comprised >90% of total binding. Kd and B max values for the two radioligands were fairly similar, with Kd values of 1–2 nM and B max values of around 7000 fmol/mg protein in hGlyT-1 membranes and 3000 fmol/mg protein in rat cortex membranes. Association of [3H]-SB-733993 was faster, with binding reaching equilibrium within 30 min compared with 90 min for [3H]-GSK931145. Dissociation was also much slower for [3H]-GSK931145 than for [3H]-SB-733993, with 50% of specific binding being dissociated by approximately 40 min and 5 min, respectively. Autoradiography studies with [3H]-GSK931145 showed widespread distribution of binding in rat brain, with generally higher binding in caudal compared with rostral areas. Initial studies in human frontal cortex membranes showed clear specific binding of [3H]-GSK931145, though with much lower density (B max 570 fmol/mg protein) and slightly lower affinity (Kd 4.5 nM) compared with rat cortex. A human brain autoradiography study showed higher specific binding in cerebellum compared with frontal cortex. All GlyT-1 inhibitors tested, as well as glycine itself, competed fully for the binding of both [3H]-SB-733993 and [3H]-GSK931145 in both hGlyT-1 and rat cortex membranes. Studies on the effect of varying NaCl concentration showed that [3H]-SB-733993 binding was reduced by >90% in the absence of added Na+ ions, whilst [3H]-GSK931145 binding was unaffected. Glycine produced concentration-dependent decreases in binding affinity of both radioligands without major changes in B max values, suggesting that both [3H]-SB-733993 and [3H]-GSK931145 bind to sites on GlyT-1 that are orthosteric to the site at which glycine itself binds. Overall, these results show that both [3H]-SB-733993 and [3H]-GSK931145 are useful radioligands for studies on GlyT-1 in both cell lines and native tissues, with [3H]-GSK931145 being the radioligand of choice for further studies on GlyT-1 expression and pharmacology. [Copyright &y& Elsevier]

Abstract: Glycine can act as either an inhibitory neurotransmitter or as a potentiator of NMDA-dependent excitatory neurotransmission. There is some evidence that glycine can have both pro- and anticonvulsant properties in various rodent models of epilepsy. In the present study we tested several glycine transporter 1 (GlyT1) inhibitors including NFPS, SSR 504734, Lu AA21279, Org 25935, SB-710622, GSK931145, as well as the glycine agonist d-serine, in the maximal electroshock threshold (MEST) test in the rat. In a series of experiments, male Sprague–Dawley rats (n =12/group) were pre-treated with a compound of interest and then received an electric shock delivered via corneal electrodes. A cohort of satellite animals (n =3/group) was also used to measure blood and brain levels of Org 25935. All GlyT1 inhibitors increased seizure thresholds dose-dependently, indicative of anticonvulsant activity. SB-710622 and GSK931145 had lower minimum effective doses (MEDs) in the MEST test than other GlyT1 inhibitors. At estimated t max, increases in dose administered were paralleled by increases in blood and brain concentrations of Org 25935. Thus, increasing extracellular concentration of glycine via inhibition of its uptake protects from electroshock-induced seizures in the rat. Whether strychnine-sensitive or strychnine-insensitive glycine binding sites are involved in this effect remains to be determined. [Copyright &y& Elsevier]

Abstract: Lead optimisation starting from the previously reported selective quinoline NK3 receptor antagonists talnetant 2 (SB-223412) and 3 (SB-222200) led to the identification of 3-aminoquinoline NK3 antagonist 10 (GSK172981) with excellent CNS penetration. Investigation of a structurally related series of sulfonamides with reduced lipophilicity led to the discovery of 20 (GSK256471). Both 10 and 20 are high affinity, potent NK3 receptor antagonists which despite having different degrees of CNS penetration produced excellent NK3 receptor occupancy in an ex vivo binding study in gerbil cortex. [Copyright &y& Elsevier]