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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]

Discusses the stereocontrolled formation of epoxy peroxide upon replacement of the carboxylic backbone by a lactam ring. Physiological activity of the endoperoxides; Epoxidation of the lactam analogues; Effect of SnCl[sub 4] on the formation of the allylic peroxides; Intramolecular cyclization of enamide.

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]

1: This study characterises the binding of a novel nonpeptide antagonist radioligand, [3H]SB-674042 (1-(5-(2-fluoro-phenyl)-2-methyl-thiazol-4-yl)-1-((S)-2-(5-phenyl-(1,3,4)oxadiazol-2-ylmethyl)-pyrrolidin-1-yl)-methanone), to the human orexin-1 (OX1) receptor stably expressed in Chinese hamster ovary (CHO) cells in both a whole cell assay and in a cell membrane-based scintillation proximity assay (SPA) format. 2: Specific binding of [3H]SB-674042 was saturable in both whole cell and membrane formats. Analyses suggested a single high-affinity site, with Kd values of 3.76±0.45 and 5.03±0.31?nM, and corresponding Bmax values of 30.8±1.8 and 34.4±2.0?pmol?mg protein-1, in whole cell and membrane formats, respectively. Kinetic studies yielded similar Kd values. 3: Competition studies in whole cells revealed that the native orexin peptides display a low affinity for the OX1 receptor, with orexin-A displaying a ~five-fold higher affinity than orexin-B (Ki values of 318±158 and 1516±597?nM, respectively). 4: SB-334867, SB-408124 (1-(6,8-difluoro-2-methyl-quinolin-4-yl)-3-(4-dimethylamino-phenyl)-urea) and SB-410220 (1-(5,8-difluoro-quinolin-4-yl)-3-(4-dimethylamino-phenyl)-urea) all displayed high affinity for the OX1 receptor in both whole cell (Ki values 99±18, 57±8.3 and 19±4.5?nM, respectively) and membrane (Ki values 38±3.6, 27±4.1 and 4.5±0.2?nM, respectively) formats. 5: Calcium mobilisation studies showed that SB-334867, SB-408124 and SB-410220 are all functional antagonists of the OX1 receptor, with potencies in line with their affinities, as measured in the radioligand binding assays, and with approximately 50-fold selectivity over the orexin-2 receptor. 6: These studies indicate that [3H]SB-674042 is a specific, high-affinity radioligand for the OX1 receptor. The availability of this radioligand will be a valuable tool with which to investigate the physiological functions of OX1 receptors.British Journal of Pharmacology (2004) 141, 340-346. doi:10.1038/sj.bjp.0705610 [ABSTRACT FROM AUTHOR]

Abstract Rationale: Orexin-A and orexin-B are hypothalamic neuropeptides derived from a 130-amino acid precursor, prepro-orexin, and are potent agonists at both the orexin-1 (OX[sub 1]) and orexin-2 (OX[sub 2]) receptors. Orexin-A has been ascribed a number of in vivo functions in the rat after intracerebroventricular (ICV) administration, including hyperphagia, neuroendocrine modulation and a role in the regulation of sleep-wake function. The in vivo role of orexin-B is not as clear. Objectives: To investigate the behavioural, endocrine and neurochemical effects of orexin-B in in-vivo tests. In a number of experiments, these effects were compared with those of orexin-A. Methods: Experiments were carried out in male, Sprague-Dawley rats with a guide cannula directed towards the lateral ventricle. The effects of orexin-B (ICV) upon grooming behaviour were compared with those of orexin-A. The effects of orexin-B upon the motor activity response to both novel and familiar environments were assessed in an automated activity monitor. Orexin-B was tested upon startle reactivity and body temperature. Further, plasma hormones and [DOPAC+ HVA]/[DA] and [5-HIAA]/[5-HT] ratios in six brain areas were measured 40 min post-orexin-B or orexin-A. Results: The clearest behavioural response to orexin-B was increased motor activity in both novel and familiar environments. Orexin-B-induced hyperactivity was blocked by an OX[sub 1] receptor antagonist, SB-334867-A, implicating OX[sub 1] receptors in this behavioural response. In common with orexin-A, orexin-B reduced plasma prolactin and failed to influence startle reactivity. However,... [ABSTRACT FROM AUTHOR]

Abstract Rationale: Orexins A and B have recently been discovered and shown to be derived from preproorexin, primarily expressed in the rat hypothalamus. Orexin-A has been ascribed a number of in vivo functions in the rat after intracerebroventricular (ICV) administration, including hyperphagia, neuroendocrine modulation and, most recently, evidence for a behavioural response characterised by an increase in grooming. Objectives: Here, we have investigated the orexin-receptor subtypes involved in the grooming response to orexin-A (3 micro g, ICV) in the rat. Methods: Male rats, habituated to clear Perspex behavioural observation boxes, were pretreated with antagonists with mixed selectivity for OX[sub 1], OX[sub 2], 5-HT[sub 2B] and 5-HT[sub 2C] receptor subtypes prior to the administration of orexin-A and the intense grooming response elicited by this peptide assessed. Results: Pretreatment of rats with a mixed OX[sub 1]/5-HT[sub 2B/2C] receptor antagonist 1-(4-methylsulfanylphenyl)-3-quinolin-4-ylurea (SB-284422), revealed a significant, but incomplete, blockade of orexin-A-induced grooming. Despite the low potency of orexin-A at 5-HT[sub 2B] and 5HT[sub 2C] receptors in vitro (pKi<5), studies were undertaken to determine whether downstream 5-HT[sub 2B] or 5-HT[sub 2C] receptors mediate in the grooming-elicited by orexin-A. Whilst the selective 5-HT[sub 2B] receptor antagonist, SB-215505 (3 mg/kg, PO, 5-HT[sub 2B], pKi=8.58; OX[sub 1], pK[sub B]<5.15) failed to effect orexin-A-induced grooming, the selective 5-HT[sub 2C] receptor antagonist, SB-242084 (1 mg/kg, IP, 5-HT[sub 2C], pKi=8.95; OX[sub 1], pK[sub B]<5.1) potently antagonised the grooming response to this peptide. This suggested that the partial blockade of... [ABSTRACT FROM AUTHOR]