Oxytocin Agonists

Although not strictly within the scope of this review, it is interesting to note that Ferring has recently reported on the properties of a non-peptidic series of oxytocin agonists. The authors envisage that the compounds may be of value in providing an oral alternative to the current practice of intravenously administered oxytocin for the induction of labour and may also have a role in the treatment of male erectile dysfunction, presumably based on the part oxytocin is believed to play in the...

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Perhaps to eliminate the propensity of the hydroxamic acid moiety to hydrolysis, Vicuron and Novartis also explored several series of a-substituted hydroxamic acids as PDF inhibitors 86 . In this study, only hydroxy and fluoro-substituents were tolerated or slightly superior to hydrogen, with thiol, methoxy, amino and larger a-substituents unsuitable. Replacement of the a-methylene with a nitrogen to provide an N-hydroxyurea as the metal-chelating group was also of no advantage, as these...

Biln 2061

Structure activity studies on compound (1), focusing on optimization at the 2-position of the quinoline and at the capping group, resulted in the identification of BILN 2061 106 , the first HCV-specific antiviral with proven antiviral effect in man 107 . Administration of BILN 2061 to patients infected with HCV genotype 1 for 2 days resulted in an impressive reduction of HCV RNA plasma levels (up to 3 log10 copies mL in a substantial proportion of patients) and established proof-of-concept in...

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2-position of the indole had a marked effect on binding, with affinity dropping up to 19-fold (cf. (282) and (285)). The high binding affinities obtained for the unsubstituted indole compounds thus support the hypothesis that H-bonding may not be the main binding feature of the AAIs and potentially aromatic stacking may be the dominant interaction. To explain the sudden drop in potency for the 2-methyl substituted indoles, the authors initiated a molecular modelling and receptor-docking study....

Indoles And Indazoles

Indomethacin morpholinyl amide (343) was found as a weak but CB2 selective agonist through a topological similarity search using WIN 55,212-2 (254a) as the template 218 . The binding affinity (K) of (343) was 435 and > 20,000 nM for hCB2 and hCB1, respectively. A subsequent SAR study revealed that N-(2,3-dichlorobenzoyl) and N-naphthoyl indole derivatives showed improved activity. Further optimisation of the substituents on the indole C3-position was also performed, and the more selective and...

Introduction

A subset of sensory nerves (those with un-myelinated axons) is characterized by a unique sensitivity to capsaicin (1), the piquant ingredient in hot chilli peppers. The excitation of these nerves is followed by a lasting refractory state, traditionally referred to as desensitization, or, under certain conditions such as neonatal treatment, by gross neurotoxicity 1 . Capsaicin-sensitive nerves function as polymodal nociceptors (their activators include noxious heat, inflammatory 'soup' and...

Acute Pancreatitis

Capsazepine attenuates interstitial oedema and neutrophil infiltration in the rat pancreas following infusion of the secretagogue cerulein 150 . HUMAN HAIR GROWTH CONTROL (ALOPECIA) AND DERMATOLOGIC DISORDERS Functional TRPV1 is expressed in keratinocytes, hair follicles, sebocytes and sweat gland cells 151, 152 . In organ cultures, activation by capsaicin of TRPV1 results in premature hair follicle regression and apoptosis 153 . This finding confers a therapeutic potential for TRPV1...

Nuclearspin Relaxation

Magnetic nuclei in a magnetic field can adopt nuclear-spin states of different energy. As a system reaches equilibrium, the population differences between the different nuclear-spin states decays exponentially through relaxation. The intensity of a resonance signal in the NMR spectrum is related to the difference in population between the two energy levels of the different nuclear-spin states. This means that the rate at which this difference returns to equilibrium and relaxation has a profound...

Cannabinoid Receptors And Endocannabinoids

The previous review article in this series described the discovery and cloning of cannabinoid CB1 and CB2 receptors and a classification of these receptors was provided in 2002 1, 6 . Cannabinoid CB1 receptors are expressed primarily within the central nervous system (CNS), where they are widely distributed. The CB1 receptor is also present in some peripheral tissues. The CB2 receptor is found mainly in cells of the immune system and exhibits 48 homology with the CB1 receptor. Both receptors...

Development And Evaluation Of Docking And Scoring

There are numerous studies evaluating the performance of docking methods and scoring functions, independently and in a variety of combinations. In most docking studies, the primary measure of success is the ability to reproduce the crystallographically observed binding modes of protein-ligand complexes. As the availability of data increases, studies are also investigating the prediction of binding affinities. A comparison is usually made to other tools typically DOCK, GOLD or FlexX. These...

References

Med. 351, 523-526. 2 World Health Organization (WHO) (2004) Annex Table 2 Deaths by cause, sex and mortality stratum in WHO regions, estimates for 2002. Geneva 3 Spellberg, M., Powers, J.H., Brass, E.P., Miller, L.G. and Edwards, J.E., Jr. (2004) Clin. Infect. Dis. 38, 1279-1286. 4 Lee, C.S., Allwine, D.A., Barbachyn, M.R., Grega, K.C., Dolak, L.A., Ford, C.W., Jensen, R.M., Seest, E.P., Hamel, J.C., Schaadt, R.D., Stapert, D., Yagi, B.H., Zurenko, G.E. and...

Screening By Xray Crystallography

In order to determine a macromolecular crystal structure, a number of processes have to be performed in a linear fashion with each stage dictating the outcome of the next. Initially, good quality protein crystals have to be made that are amenable to X-ray diffraction analysis. The routine use of cryopreservation techniques 4 over the last 10 years has meant that the required size of usable protein crystal has decreased, removing much of the burden of teasing out ordered growth conditions for...

Comparative Homology Modelling

Of the 517 protein kinases in the human kinome 116 , structures are publicly available for < 10 of the different enzymes. In the absence of experimental data, construction of homology models based on known structures has proven a reliable method for generating 3D information. How, then, are the models built and what are the limitations of the models especially as applied to the family of protein kinases There are several stages to the construction of the homology model, probably the most...

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There is extensive patent literature claiming oxytocin antagonists. In many of these examples, the principal focus appears to be on vasopressin, with oxytocin as a secondary claim and where biological data are included, oxytocin antagonist activity is often quite weak. A number of companies do, however, have substantive oxytocin antagonist patents, including Sanofi-Aventis, Serono, Wyeth and Yamanouchi. Sanofi-Aventis, through the research activities of the heritage company Sanofi-Synthelabo,...