Electron transfer from Proteus vulgaris to a covalently assembled, single walled carbon nanotube electrode functionalised with osmium bipyridine complex: application to a whole cell biosensor

We report the fabrication and use of electrodes constructed from single walled carbon nanotubes (SWCNTs) chemically assembled on a carbon surface and functionalised with an osmium(II) bipyridine complex (Osbpy). The ability of the electrodes to transduce biologically generated currents from Proteus vulgaris has been established. Our investigations show that there are two contributions to the current: one from electroactive species secreted into solution and another from cell redox sites. The modified electrode can be used to monitor cell metabolism, thereby acting as a whole cell biosensor. The biosensor was used in a 1-h assay to investigate the toxicity of ethanol, sodium azide and the antibiotic ampicillin and gave quantitative data that were closely correlated with standard cell plate viability assays. The results provide proof of principle that the whole cell biosensor could be used for high throughput screening of antimicrobial activity. One of the modified electrodes was used for approximately 1000 measurements over four months demonstrating the robustness of the system.     

Discovery of PF-184563, a potent and selective V1a antagonist for the treatment of dysmenorrhoea. The influence of compound flexibility on microsomal stability

The V1a receptor has emerged as an attractive target for a range of indications including Raynaud's disease and dysmenorrhoea. As part of an effort to discover a new class of orally active V1a antagonist, we optimised a highly lipophilic, metabolically unstable lead into a range of potent, selective and metabolically stable V1a antagonists. In this communication, we demonstrate the series-dependent effect of limiting the number of rotatable bonds in order to decrease Cytochrome P450-mediated metabolism. This effort culminated in the discovery of PF-184563, a novel, selective V1a antagonist with excellent in vitro and in vivo properties.     

The design and synthesis of a novel series of indole derived selective ET(A) antagonists.

Conformational constraint has been used as the key design element in the identification of a series of potent and selective ET(A) antagonists. The most potent antagonist, 32, (ET(A) IC(50)=0.55nM) is 722-fold selective over the ET(B) receptor, as measured by binding experiments.     

The discovery of UK-369003, a novel PDE5 inhibitor with the potential for oral bioavailability and dose-proportional pharmacokinetics

This paper describes our recent efforts to design and synthesise potent and selective PDE5 inhibitors and the use of in vitro predictors of clearance, absorption and permeability to maximise the potential for dose-proportional pharmacokinetics and good oral bioavailability in man. Optimisation of the preclinical profile resulted in the identification of UK-369003 (19a) and its nomination as a clinical candidate. The clinical pharmacokinetic and safety profile has enabled us to progress the compound to test its efficacy in patients with lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) and a paper describing its efficacy has recently been published.     

Effects of Salbutamol and Isoprenaline Phenylephrine in Reversible Airways Obstruction

Ventolin (salbutamol) and Medihaler-Duo (isoprenaline/phenylephrine combination) standard pressurized inhalers were used to administer doses of two or six “puffs” to 16 patients with known reversible airways obstruction. The doses were administered in random order over two days. Both the Ventolin and Medihaler-Duo inhalers substantially increased FEV₁, but in the doses used salbutamol was more effective than isoprenaline/phenylephrine (P < 0·01). There was no significant difference between two and six puffs of salbutamol, though there seemed to be an advantage of six puffs of isoprenaline/phenylephrine over two puffs (P < 0·05). Adrenaline (1/1,000) 0·5 ml and atropine 0·6 mg produced similar increases in FEV₁ to those produced by salbutamol.The Pao₂ fell more than 5 mm Hg in three patients after salbutamol and in three after isoprenaline/phenylephrine. There was no significant fall in mean Pao₂ in any of the treatment groups. It is concluded that the Ventolin inhalant, administered in the conventional dose of two puffs, is as effective a bronchodilator as subcutaneous adrenaline and atropine, is more effective than the Medihaler-Duo, and is without detectable side effects.     

毒蕈碱型乙酰胆碱受体的鼻黏膜效应

副交感神经参与鼻黏膜腺体和血管的功能调节.当各种异物、细菌、病毒或真菌侵入机体时, 鼻黏膜微环境发生改变, 这种变化刺激副交感神经释放乙酰胆碱.后者与调节鼻腺体和血管的毒蕈碱型乙酰胆碱受体 (M-ChR) 结合,导致鼻炎流涕和鼻塞.这种整体调节反射对下呼吸道起重要的防御性保护作用. 目前发现五种M-ChR亚型(M1-至M5- ChR),鼻黏膜有M1-至 M3- ChR亚型.高密度的M1-和M3- ChR共存于黏膜下腺黏液和浆液细胞, M3-ChR主要分布于血管.M-ChR对鼻腺体和血管的直接调节作用是通过细胞内腺苷酸环化酶和磷酯酶C激活.