Letters in Drug Design & Discovery - Volume 4, Issue 3, 2007

(-)-Epigallocatechin gallate (EGCG) has a sedative effect acting through γ-aminobutyric acid (GABA)A receptors in the brain, but it is unclear what structural components of the molecule are necessary for its action. To investigate the necessity of the galloyl group on the sedation induced by EGCG, the effect of EGCG was compared with (-)-epigallocatechin (EGC) in which the galloyl group is removed from EGCG. Intracerebroventricular (i.c.v.) injection of EGC, as well as EGCG, induced, and the effect of EGC were blocked by the GABAA receptor antagonist picrotoxin. It is concluded that catechins have a sedative effect acting through GABAA receptors under an acute stress condition irrespective of the presence of the galloyl group.

The effect of pharmacones clathration with glycosides results in significant decrease of drug agent dosage. We investigated the clathrates of hypotensive agent Nifedipine with glycyrrhizic acid, which was prepared in molecular proportion 1:4 respectively. Present study was carried out on the calcium channels on neurons of Lymnaea stagnalis mollusc.

A rapid and efficient synthesis of estrogenic dimers, with 45% overall yield, is described. The new molecules possess two estrone units linked at position 16, with either an alkyl chain or a polyethylene glycol chain. The biological activity of these compounds was evaluated in vitro on estrogen dependent and independent human breast tumor cell lines: MCF-7 and MDA-MB-231.

In this study, we describe, for the first time, the synthesis and photophysical and microbiological investigation of ruthenium trischelate diimine complexes designed so as to possess properties specifically suited for use in Photodynamic antimicrobial chemotherapy (PACT). Of the three compounds investigated, one ([Ru(dmob)3]Cl2) has demonstrated considerable promise as a photosensitiser for use in PACT. As a result, this compound is now the subject of comprehensive chemical, toxicological and formulation studies.

We report the search for non-steroidal inhibitors of 17β-hydroxysteroid dehydrogenase, in particular, for types 1 and 3. The results show that the synthesised compounds based on the biphenyl backbone were good inhibitors of 17β-HSD1, but were weak inhibitors of 17β-HSD3. The compounds were evaluated against 3β-HSD but showed weak inhibition.

High throughput screening identified a pyrrolidinone containing acidic functionality as a CCR2 antagonist of modest affinity. We describe initial SAR around this hit, including solution phase parallel synthesis for analog preparation, and we describe identification and characterization of an analog subsequently selected as a viable lead molecule for further optimization.

The CYP3A4 inhibition SVM classification model achieved high prediction accuracy, which can be used as high throughput computational filter for identifying CYP3A4 inhibition liability. It's demonstrated that the distance to the separating surface in the feature space can be used as valuable confidence index for the prediction of each compound.

Lantadene D was semi-synthetically prepared by functionalizing 22β-hydroxyoleanonic acid and screened for cytotoxicity against four human cancer cell lines (HL-60, HeLa, Colon 502713 and Lung A-549). It was further evaluated for its inhibitory profile against two-stage carcinogenesis in Swiss albino mice.

Dependence can be induced and measured in vitro by using guinea-pig ileum. After a brief exposure to opioids, tissues from untreated animals, show a strong naloxone-induced contracture indicating that the cellular mechanisms of dependence may occur very rapidly following occupation of receptors and that these mechanisms operate within the myenteric plexus. Several observations indicate that acethilcoline (Ach) is involved in pharmacological effects of morphine and it is one of neurotransmitters widely involved in the expression of opioid withdrawal. This is confirmed by data showing that atropine, a well known muscarinic receptor, is able to block the symptoms of opiate withdrawal. Five subtypes muscarinic receptors, M1-M5, have been identified by pharmacological studies. The availability of agonists and antagonists for M1-M5, provides powerful tools that can be used to determine the roles of these receptor types in mediating some of physiological and pharmacological effects of muscarinic receptors in the central nervous system (CNS). The experiments described here were undertaken to provide insight into the role of M1-M5 muscarinic receptors subtypes in mediating opioid withdrawal. Therefore, the effects exerted by M1-M5 muscarinic receptors antagonists on the acute opiate withdrawal induced by opioids were investigated in vitro. Following a 4 min in vitro exposure to morphine or DAGO or U50-488H the guinea-pig isolated ileum exhibited a strong contracture after the addition of naloxone. The addition of pirenzepine, the M1 muscarinic receptor antagonist (1x10-8-5x10-8-1x10-7 M) 10 min before each opioid agonist produced a concentration-dependent reduction of the opioid withdrawal. Very similar results were obtained with metoctramine (M2 muscarinic receptor antagonist) with 4-DAMP (M3 muscarinic receptor antagonist) with himbacine (M4 muscarinic receptor antagonist) and PD 102807 (M5 muscarinic receptor antagonist). The results of our experiments indicate that M1-M5 muscarinic receptors antagonists are able to reduce opioid withdrawal in vitro thus confirming an important functional interaction between the muscarinic system and opioid withdrawal.

Two new regioisomers acyclonucleosides bearing 1,2,4-triazole rings as the base moiety were synthesised with aliphatic side chain [(2-acetoxyethoxy)methyl]-bromide under solid-liquid phase transfer catalysis (S.L.P.T.C.) and under silylation method. Biological evaluation of all product revealed they were inactive against various RNA and DNA viruses in cell cultures. Structure activity relationship studies (SAR) indicate that introduction of acyclovir arm in N1 or N2 position of 1,2,4-triazole has not any impact on the antiviral activity.

High throughput screening (HTS) has become a pivotal part of drug discovery for identifying potential lead molecules for specific disease targets. The success of screening is measured by several factors including the throughput and cost of the assays, but ultimately by the number of HTS hits that progress forward through the drug discovery pipeline. Miniaturization of assays by conversion from 96- to 384- to 1536- wells to well-less platforms, and the utilization of automated equipments are methodologies implemented to increase the throughput and reduce the cost of the screen. Pooling of test compounds is also an effective, though controversial method to enhance screening throughput while reducing reagent costs. Herein, we describe specific measures implemented at Abbott Laboratories to enhance the efficiency of 10- mixture orthogonal screening, and the strategy developed to reduce the rate of false positives and eliminate false negatives. Results from a comparison study of mixtures versus single compound screening will be discussed for three distinct screening formats: a GPCR functional assay, a GPCR binding assay and a tyrosine kinase assay.

Since its first description nearly a decade ago, mammalian target of rapamycin (mTOR) has emerged as a critical regulator of cell size and growth in normal and neoplastic conditions. Many cancers rely on mTOR pathway members for their survival, and these proteins thus form attractive targets with wide potential therapeutic indices. Understanding the role of mTOR in lymphomagenesis is complicated by the intricacy of upstream and downstream components as well as potential differences due to the inherent heterogeneity of lymphoma subtypes. Nevertheless, significant data supports a central role of mTOR pathway in lymphoma. Several lymphoma subtypes harbor PTEN deletions, Akt overexpression, or increased eIF4E. Rapamycin is the prototypical mTOR inhibitor, and has clear anti-tumor effects in many lymphoma preclinical models. Newer rapamycin analogs, including the prodrugs temsirolimus and everolimus, and the non prodrug AP23573, are in clinical trials with preliminary, but promising, activity in hematologic malignancies. The limited treatment options for many patients with relapsed lymphomas coupled with the encouraging activity of mTOR inhibitors warrant ongoing attention and clinical development of these agents.

In this paper we report the synthesis of a new series of benzenesulfonamides and the evaluation of their binding properties on ETAh and ETBh receptor subtypes. Some new derivatives behave as selective ETAh receptor ligands and among them, 2-{[(4-chloro-3-methyl-5-isoxazolyl)amino]sulfonyl}-N-(2,4,6- trimethylphenyl)benzamide (23) was the most interesting.