Medicina

The 5-HT7R is the most recent addition to the burgeoning family of serotonin receptors. Preliminary evidences suggest that it may be involved in depression, control of circadian rhythms, and relaxation in a variety of vascular smooth muscles, indicating the high potential of 5-HT7R ligands as new therapeutic drugs. During the last four years several selective 5-HT7R antagonists have been discovered, and we have recently contributed to this field with the definition of a pharmacophoric hypothesis for 5-HT7R antagonism and a computational model of ligand-receptor interaction of new naphtholactam and naphthosultam derivatives acting at this receptor. This article will review the development of 5-HT7R antagonists with an emphasis on selective antagonists, their structural requirements and ligand-receptor interactions, as well as the potential therapeutic opportunities surrounding 5-HT7R ligands.

A mixture of five tetracycline (TC) derivatives: minocycline (MC), demeclocycline (DMCTC), doxycycline (DC), and sancycline (SC), as well as each TC derivative from its main degradation product were separated by capillary zone electrophoresis (CZE). The influence of the pH and the concentration and nature of the background electrolyte (BGE) on the separations was investigated. Ethylenediaminetetraacetic acid (EDTA; 1mM) was used as additive in a 25 mM phosphate buffer (pH 2.3) because this BGE enabled the rapid separation of the TC derivatives and of each TC derivative from its respective degradation product in less than 6 min. After optimization of the separation conditions, the analytical characteristics of the method were investigated. The parameters involved were linearity, precision (repeatability and reproducibility), and limits of detection (LODs). LODs obtained for the five TC derivatives studied were about 3 g/mL. Finally, the CZE method developed was applied to study the stability of TC derivatives and to analyze the TC derivative content in three different pharmaceutical preparations.

With the aim of fuelling open-source, translational, early-stage drug discovery activities, the results of the recently completed antimycobacterial phenotypic screening campaign against Mycobacterium bovis BCG with hit confirmation in M. tuberculosis H37Rv were made publicly accessible. A set of 177 potent noncytotoxic H37Rv hits was identified and will be made available to maximize the potential impact of the compounds toward a chemical genetics/proteomics exercise, while at the same time providing a plethora of potential starting points for new synthetic lead-generation activities. Two additional drug-discovery- relevant datasets are included: a) a drug-like property analysis reflecting the latest lead-like guidelines and b) an early lead-generation package of the most promising hits within the clusters identified.

A rapid and simple capillary zone electrophoresis (CZE) method for the determination of terbinafine and eight of its main metabolites after incubation with rat hepatic S9 fraction was developed. The effect of the concentration and type of the running electrolyte as well as of the addition of an organic solvent were studied with emphasis on selectivity and sensitivity. All nine components obtained (unmetabolized terbinafine and up to eight of its metabolites) are baseline resolved in less than 4 minutes using a 0.05 M phosphate buffer (pH 2.2) without additives, after a solid-phase clean-up procedure of these in-vitro samples. In addition, under the conditions described, no endogenous components of the sample interfere at the detection wavelength chosen. After optimization of the separation conditions, some analytical characteristics of the developed CZE method were investigated. A limit of detection of only 0.08 lg/mL was obtained for terbinafine using a standard solution. Finally, the use of on-line CZE/ diode array detection enabled to identify tentatively the presence of unmetabolized parent terbinafine and its metabolites in the mixture of nine components separated.

Plasmodium falciparum lactate dehydrogenase (PfLDH) is essential for ATP generation. Based on structural diVerences within the active site between P. falciparum and human LDH, we have identiWed a series of heterocyclic azole-based inhibitors that selectively bind within the PfLDH but not the human LDH (hLDH) active site and showed anti-malarial activity in vitro and in vivo. Here we expand on an azole, OXD1, from this series and found that the anti-P. falciparum activity was retained against a panel of strains independently of their anti-malarial drug sensitivity proWle. Trophozoites had relatively higher PfLDH enzyme activity and PfLDH-RNA expression levels than rings and were the most susceptible stages to OXD1 exposure. This is probably linked to their increased energy requirements and consistent with glycolysis being an essential metabolic pathway for parasite survival within the erythrocyte. Further structural elaboration of these azoles could lead to the identiWcation of compounds that target P. falciparum through such a novel mechanism and with more potent anti-malarial activity.

Models to predict binding affinities to human serum albumin (HSA) should be very useful in the pharmaceutical industry to speed up the design of new compounds, especially as far as pharmacokinetics is concerned. We have experimentally determined through high-performace affinity chromatography the binding affinities to HSA of 95 diverse drugs and druglike compounds. These data have allowed us the derivation of quantitative structure-activity relationship models to predict binding affinities to HSA of new compounds on the basis of their structure. Simple linear, one-variable models have been derived for specific families of compounds (r2 g 0.80; q2 g 0.62): â-adrenergic antagonists, steroids, COX inhibitors, and tricyclic antidepressants. Also, global models have been derived to be applicable to the whole medicinal chemical space by using the full database of HSA binding constants described above. For this aim, a genetic algorithm has been used to exhaustively search and select for multivariate and nonlinear equations, starting from a large pool of molecular descriptors. The resulting models display good fits to the experimental data (r2 g 0.78; LOF e 0.12). In addition, both internal (cross validation and randomization) and external validation tests have demonstrated that these models have good predictive power (q2 g 0.73; PRESS/SSY e 0.23; r2 g 0.82 for the external set). Statistical analysis of the equation populations indicates that hydrophobicity (as measured by the ClogP) is the most important variable determining the binding extent to HSA. In addition, structural factors (especially the topological 6øring index and some Jurs descriptors) also frequently appear as descriptors in the best equations. Therefore, binding to HSA turns out to be determined by a combination of hydrophobic forces together with some modulating shape factors. This agrees with X-ray structures of HSA alone or bound to ligands, where the binding pockets of both sites I and II are composed mainly of hydrophobic residues.