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Khan M.A.,University of Bath | Lowe J.P.,University of Bath | Johnson A.L.,University of Bath | Stewart A.J.W.,Prosidion Ltd | Lewis S.E.,University of Bath
Chemical Communications | Year: 2011

A cyclohexadiene ligand prepared by microbial arene 1,2-dihydroxylation undergoes spontaneous rearrangement upon complexation to tricarbonyliron(0). Subsequent iron removal affords a novel route to formal arene 2,3-dihydroxylation products enantiomeric to those obtainable by direct microbial arene oxidation. © 2011 The Royal Society of Chemistry. Source


Wang X.,University of Reading | Horswill J.G.,Prosidion Ltd | Whalley B.J.,University of Reading | Stephens G.J.,University of Reading
Molecular Pharmacology | Year: 2011

1-(4-Chlorophenyl)-3-[3-(6-pyrrolidin-1-ylpyridin-2-yl)phenyl] urea (PSNCBAM-1) has recently been described as a cannabinoid CB1 receptor allosteric antagonist associated with hypophagic effects in vivo; however, PSNCBAM-1 effects on CB 1 ligand-mediated modulation of neuronal excitability remain unknown. Here, we investigate PSNCBAM-1 actions on CB 1 receptor-stimulated guanosine 5′-O-(3-[ 35S]thio)triphosphate ([ 35S]GTPγS) binding in cerebellar membranes and on CB 1 ligand modulation of presynaptic CB 1 receptors at inhibitory interneuron-Purkinje cell synapses in the cerebellum using whole-cell electrophysiology. PSNCBAM-1 caused noncompetitive antagonism in [ 35S]GTPγS binding studies, with higher potency against the CB receptor agonist (-)-cis-3-[2-hydroxy-4-(1,1-dimethyl heptyl)phenyl]-trans-4-(3- hydroxypropyl)cyclohexanol (CP55940) than for R(+)-[2,3-dihydro-5-methyl-3- [(morpholinyl)methyl]-pyrrolo[1,2,3,-de]-1,4-benzoxazinyl]-(1-naphthalenyl) methanone mesylate] [WIN55,212-2 (WIN55)]. In electrophysiological studies, WIN55 and CP55940 reduced miniature inhibitory postsynaptic currents (mIPSCs) frequency but not amplitude. PSNCBAM-1 application alone had no effect on mIPSCs; however, PSNCBAM-1 pretreatment revealed agonist-dependent functional antagonism, abolishing CP55940-induced reductions in mIPSC frequency but having no clear effect on WIN55 actions. The CB 1 antagonist/inverse agonist N-(piperidin-1-yl)-1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-1H- multipyrazole-3-carboxamide (AM251) increased mIPSC frequency beyond control; this effect was reversed by PSNCBAM-1. PSNCBAM-1 pretreatment also attenuated AM251 effects. Thus, PSNCBAM-1 reduced CB 1 receptor ligand functional efficacy in the cerebellum. The differential effect of PSNCBAM-1 on CP55940 versus WIN55 actions in [ 35S]GTPγS binding and electrophysiological studies and the attenuation of AM251 effects are consistent with the ligand-dependence associated with allosteric modulation. These data provide the first description of functional PSNCBAM-1 allosteric antagonist effects on neuronal excitability in the mammalian central nervous system (CNS). PSNCBAM-1 allosteric antagonism may provide viable therapeutic alternatives to orthosteric CB 1 antagonists/inverse agonists in the treatment of CNS disease. Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics. Source


Davies J.J.,University of Oxford | Krulle T.M.,Prosidion Ltd | Burton J.W.,University of Oxford
Organic Letters | Year: 2010

(Figure presented) An efficient total synthesis of the novel botryococcene-related hydrocarbon 7,11-cyclobotryococca-5,12,26-triene is reported that uses, as a key step, an oxidative radical cyclization of a 4-pentenyl malonate for the synthesis of a [3.3.0]-bicyclic γ-lactone. © 2010 American Chemical Society. Source


Patent
PROSIDION Ltd | Date: 2010-03-12

The present invention is directed to therapeutic compounds which have activity as agonists of GPR119 and are useful for the treatment of metabolic disorders including type II diabetes.


Patent
PROSIDION Ltd | Date: 2010-03-12

The present invention is directed to therapeutic compounds of the following formula (I) which have activity as agonists of GPR119 and are useful for the treatment of metabolic disorders including type II diabetes.

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