Identification and synthesis of novel inhibitors of mycobacterium ATP synthase.

A non-diaryl quinoline scaffold 6,7-dihydropyrazolo[1,5-a]pyrazin-4-one was identified by screening of diverse set of compounds against M. smegmatis ATP synthase. Herein, we disclose our efforts to develop the structure activity relationship against Mycobacterium tuberculosis (Mtb.

Pharmacology of a novel, orally active PDE4 inhibitor.

Background: Intracellular cyclic adenosine monophosphate (cAMP) in inflammatory cells and airway smooth muscle is critical to the modulation of inflammatory response generation. Phosphodiesterase 4 (PDE4), an enzyme that catalyzes cAMP degradation, is therefore being actively explored as a molecular target for the treatment of airway inflammation, particularly asthma and chronic obstructive pulmonary disease. The field has undergone major advances in optimizing generation of compounds with a safe therapeutic margin; however, most PDE4 inhibitors tested so far have unacceptable side effects, particularly nausea and vomiting.

Functional screening of adrenergic receptors by measuring intracellular calcium using the FlexStation scanning fluorimeter.

In this study we test whether functional screening of compounds to adrenergic G protein-coupled receptors (GPCRs) would provide data that correlated significantly with radiolabeled binding data, thereby permitting researchers to replace expensive radioligand-binding experiments with non-radioactive screening. An increase in intracellular calcium levels represents an important second messenger signal for several recombinant GPCRs. In this study, we describe the affinities of three alpha adrenoceptor antagonists (terazosin, tamsulosin and alfuzosin), determined by monitoring the changes in intracellular calcium levels and comparing them with their radioligand-binding affinities.

Ratiometric Ca+2 measurement in human recombinant muscarinic receptor subtypes using the Flexstation scanning fluorometer.

In modern drug discovery, numerous assay formats are available to screen and quantitate receptor-ligand interactions. Radioactive assays are "gold standard" because they are fast, easy, and reproducible; however, they are hazardous, produce radioactive waste, require special lab conditions, and are expensive on a large scale. Thus, it provides a lot of importance to the "mix & measure" assays that have an optical readout.

RBx 6198: a novel alpha1-adrenoceptor antagonist for the treatment of benign prostatic hyperplasia.

The present study, investigates the effect of RBx 6198, 2-{3-[4-(2-Isopropoxy-phenyl)-piperazin-1-yl]-propyl}-3a, 4, 7, 7a-tetrahydro-isoindole-1, 3,-dione, a novel alpha(1)-adrenoceptor antagonist, in both in vitro and in vivo test systems. RBx 6198 is a potent (nanomolar affinity) alpha(1A)-adrenoceptor antagonist with demonstrable uroselectivity in anaesthesized dog model. In radioligand binding studies using human recombinant receptors, RBx 6198 exhibited high selectivity (approximately 50 fold) for the alpha(1A)-adrenoceptor subtype as compared to alpha(1B)-adrenoceptor subtype.

Optimization and validation of a reporter gene assay for screening of phosphodiesterase inhibitors in a high throughput system.

Phosphodiesterases (PDEs) hydrolyze cyclic nucleotides, cyclic adenosine monophosphate (cAMP) and guanosine monophosphate (cGMP) into inactive 5' monophosphates, and exist as 11 families. Inhibitors of PDEs allow the elevation of cAMP and cGMP, which leads to a variety of cellular effects including airway smooth muscle relaxation and inhibition of cellular inflammation or of immune responses. PDE4 inhibitors specifically prevent the hydrolysis of cAMP.

An improved zinc cocktail-mediated fluorescence polarization-based kinase assay for high-throughput screening of kinase inhibitors.

During the past few years, high-throughput screening (HTS) has provided a useful resource to researchers involved in the development of kinase inhibitors as a novel therapeutic modality. However, with all the choices among kinase assays, there is not yet a one-size-fits-all assay. Therefore, selection of a specific kinase assay is a daunting task.

Molecular cloning, stable expression and cellular localization of human alpha1-adrenergic receptor subtypes: effect of charcoal/dextran treated serum on expression and localization of alpha1D -adrenergic receptor.

The cDNAs encoding for three subtypes of adrenergic receptors, alpha1A-, alpha1B- and alpha1D-ARs, were cloned and expressed in HEK 293 cells. Expression of alpha1A- and alpha1B-AR subtypes in HEK 293 cells was stable even with increased passages but that of alpha1D-AR was not. Cellular localization studies using immunofluorescence and flow cytometry revealed that expression of alpha1A- and alpha1B-ARs was primarily localized on the cell membrane whereas expression of alpha1D-AR was predominantly intracellular.

WITHDRAWN: Derivatives of cis-1,2,3,6-tetrahydrophthalimide for the treatment of benign prostatic hyperplasia.

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Benign prostatic hyperplasia: an insight into current investigational medical therapies.

Benign prostatic hyperplasia (BPH) is a leading disorder of the elderly male population that is characterised by a progressive enlargement of prostatic tissue, resulting in obstruction of the proximal urethra and causing urinary flow disturbances. The pathophysiology of BPH associated with lower urinary tract symptoms is characterised by increased adrenergic tone (dynamic component) leading to smooth muscle contraction and prostatic overgrowth due to androgenic stimulation (static component); therefore, the therapeutic armamentarium of BPH can be broadly divided into antiadrenergic and antiandrogenic approaches. alpha1-Adrenoceptor antagonists and 5alpha-reductase inhibitors are well-established representatives of the two categories, respectively.