Current Medicinal Chemistry - Volume 11, Issue 24, 2004

The discovery of the two isoenzymes COX-1 and COX-2 and the knowledge of their function, localisation and regulation has initiated the development of COX-2 selective inhibitors (coxibs). Inducible COX-2 at the peripheral site of inflammation has been detected in the early 1990s, the involvement of recently detected spinal COX-2 has led to new insights into mechanisms of pain and may explain analgesic and antipyretic properties of COX-2 selective inhibitors. The coxibs rofecoxib and celecoxib have been introduced into therapy and seem to offer some advantages over the classical non-selective NSAIDs. The search for new COX-2 inhibitors is going on, the development of etoricoxib and lumiracoxib is a step ahead concerning efficacy, tolerability and safety. Until today COX-2 selective inhibitors have found their place in therapy of arthritis, osteoarthritis, dysmenorrhea and acute pain. A new paradigm in pain therapy seems to justify their use in perioperative settings in a preemptive or multimodal therapeutical strategy. In the future COX-2 selective inhibitors as opioid sparing agents could become an important tool in pain therapy. Even a therapeutical benefit of COX-2 selective inhibitors in the treatment of Alzheimer's Disease or in the prevention or treatment of colorectal or prostate cancer is presently intensely investigated. Recently some authors reported on COX-3, a splicing variant of COX-1. If COX-3 really represents the target for acetaminophen must be called into question.

Synthetic ether-linked analogues of phosphatidylcholine and lysophosphatidylcholine, collectively named as antitumour lipids (ATLs), were initially synthesized in the late 60s, but have attracted a renewed interest since the finding that the ether lipid 1-O-octadecyl-2-O-methyl-rac-glycero-3- phosphocholine (ET-18-OCH3, edelfosine), a synthetic analogue of 2-lysophosphatidylcholine considered the ATL prototype, induces a selective apoptotic response in tumour cells, sparing normal cells. Unlike most chemotherapeutic agents currently used, ET-18-OCH3 does not interact with DNA, but act at the cell membrane, and thereby its effects seem to be independent of the proliferative state of target cells. Each part of the molecular structure of ET-18-OCH3 is important for its optimal proapoptotic activity. Recent progress has unveiled the molecular mechanism underlying the apoptotic action of ET-18-OCH3, involving membrane rafts and Fas / CD95 death receptor, and has led to the proposal of a two-step model for the ET-18-OCH3 selective action on cancer cells, namely: a) ET-18-OCH3 uptake into the tumour cell, but not in normal cells; b) intracellular activation of Fas / CD95 through its translocation and capping into membrane rafts. ET-18-OCH3 constitutes the first antitumour drug acting through the intracellular activation of the Fas / CD95 death receptor. Computational docking studies have allowed us to propose a molecular model for the putative interaction of ET-18-OCH3 with the intracellular Fas/CD95 death domain. This novel mechanism of action represents a new way to target tumour cells in cancer chemotherapy and can be of interest as a new framework in designing novel and more selective proapoptotic antitumour drugs.

This review gives a brief overview of the expression patterns, molecular pharmacology and physiological roles of the vanilloid receptor 1 (VR1). Particular emphasis is given to the therapeutic utility of VR1 modulators. Small molecule agonists of VR1, including capsaicin and RTX, are currently utilized for a number of clinical syndromes, including intractable neuropathic pain, spinal detrusor hyperreflexia, and bladder hypersensitivity; however, antagonists of VR1 have yet to reach the clinic. While the classic VR1 antagonist, capsazepine has proven a useful tool for unraveling the molecular pharmacology of VR1, in vivo studies with this compound have had limited success due to poor pharmacokinetic properties and species selectivity issues. With the cloning of VR1 in 1997, the pharmaceutical community has been provided a molecular target for high throughput screening and small molecule lead discovery and optimization. As a result, resurgence in the interest of VR1 antagonists has given way to many new pharmacological agents that may provide better tools to probe VR1 physiology, and ultimately yield promising therapeutic agents.

The cellular and molecular mechanisms underlying cardiovascular dysfunctions are widely unknown. Basically, pathological changes in the cardiovascular system arise from protein alterations. Proteomics comprises a set of tools for the large-scale study of gene expression at the protein level thereby allowing for the identification of protein alterations responsible for the development and the pathological outcome of diseases including those of the cardiovascular system. In principle these alterations include those of suitable candidates for drug targets and disease biomarkers as well as therapeutic proteins / peptides. Since gene therapy depends on the function of a therapeutic protein encoded by a “therapeutic” gene proteomic analyses also provide the basis for the design and application of gene therapies. Proteomic technologies allow to identify not only proteins but also the nature of their posttranslational modifications thus enabling the elucidation of signal transduction pathways and their deregulation under pathological conditions. The linkage of information about proteome changes with functional consequences lead to the development of functional proteomic studies. Functional proteomic analyses will particularly help to better understand the relations between proteome changes and cardiovascular dysfunctions. The storage and administration of experimental data obtained by the application of proteomic analyses is supported by species- and tissue-specific protein databases and specific software. Publications in this field are reviewed in this paper.

The cellular mechanism of action of tedisamil (KC-8857) (TED), a novel antiarrhythmic / antifibrillatory compound, was studied on transmembrane currents in guinea pig, rabbit and dog ventricular myocytes by applying the patch-clamp and the conventional microelectrode technique. In guinea pig myocytes the rapid component of the delayed rectifier potassium current (IKr) was largely diminished by 1 μM TED (from 0.88±0.17 to 0.23±0.07 pA / pF, n=5, p<0.05), while its slow component (IKs) was reduced only by 5 μM TED (from 8.1±0.3 to 4.23±0.07 pA / pF, n=5, p<0.05). TED did not significantly change the IKr and IKs kinetics. In rabbit myocytes 1 μM TED decreased the amplitude of the transient outward current (Ito) from 20.3±4.9 to 13.9±2.8 pA / pF (n=5, p<0.05), accelerated its fast inactivation time constant from 8.3±0.6 to 3.5±0.5 ms (n=5, p<0.05) and reduced the ATP-activated potassium current (IKATP) from 38.2±11.8 to 18.4±4.7 pA / pF (activator: 50 μM cromakalim; n=5, p<0.05). In dog myocytes 2 μM TED blocked the fast sodium current (INa) with rapid onset and moderately slow offset kinetics, while the inward rectifier potassium (IK1), the inward calcium (ICa) and even the Ito currents were not affected by TED in concentration as high as 10 μM. The differences in Ito responsiveness between dog and rabbit are probably due to the different α-subunits of Ito in these species. It is concluded that inhibition of several transmembrane currents, including IKr, IKs, Ito, IKATP and even INa, can contribute to the high antiarrhythmic / antifibrillatory potency of TED, underlying predominant Class III combined with I A / B type antiarrhythmic characteristics.

In recent years several mutations and sequence polymorphisms of the glucocorticoid receptor gene have been described. The majority of mutations have been found in patients with a rare endocrinological abnormality, the glucocorticoid resistance syndrome. In addition, some sequence polymorphisms have been considered to contribute to various diseases, but unambiguous correlations have not been established yet. Here we present the results of an in silico study, which revealed previously undescribed sequence variants of the glucocorticoid receptor gene. Although the three-dimensional structure of the DNA-binding domain of the glucocorticoid receptor has been known for several years, the crystal structure of the ligand-binding domain of the receptor has been published only recently. Using a comparative protein modelling, we analysed the structural relevance of known mutations as well as novel sequence variants discovered by our in silico approach in the ligand-binding domain of the glucocorticoid receptor. We conclude that comparative protein modelling of these mutant receptor variants offers a useful means to predict the functional consequences of amino acid replacements and to correlate structural abnormalities with clinical findings.

The scope of this review encompasses the importance of furocoumarins and the most important developments in this field that have been made in recent years, with particular emphasis placed on the aspects related to medicinal chemistry. A concise and exhaustive overview is given regarding the methods used for the synthesis of these compounds, new furocoumarins isolated from natural sources, and the most significant biological properties associated with these molecules. The section describing the synthetic methods is organized on the basis of the key step used for the formation of the two different oxygenated rings. In this respect there are three possibilities: (i) formation of the furan ring onto the coumarin, (ii) formation of the pyrone ring onto the benzofuran and (iii) the simultaneous formation of both oxygenated rings onto a benzene unit. The most recent preparative approaches are discussed along with modifications or improvements to methods that, though not particularly new, are still commonly used. The recently discovered natural furocoumarins are focused and presented in tables that provide information about its structure and source. The discussion of the biological importance of furocoumarins mainly focuses on their more relevant applications in photochemotherapy, but also provides examples of their versatility in a range of applications in the fields of biology and pharmacology.

The replacement of peptide bond is an important segment in the synthesis of peptidomimetics, because this modification may result in the preparation of biologically active analogues with improved properties, especially regarding bioavailability and metabolical stability. The introduction of sulfonamide group increases polarity of a molecule and the hydrogen-bond donor properties as a sulfonamide N-H is more acidic (pKα=11-12) than carboxamide. Furthermore, due to geometry of sulfur atom the sulfonamido bond shows structural similarity to the tetrahedral transition state present as an intermediate in the enzymatic hydrolysis of an amide bond thus making these compounds candidates in the development of new drugs. Recent advances in the synthesis of building blocks for sulfonamidopeptides, such as α or β- substituted aminoalkylsulfonates and efficient methods for the formation of sulfonamide bond have enabled the preparation of large number of oligomers with potential applications on various fields. These methods have been applied for the synthesis of oligopeptidosulfonamides, catalysts, receptor molecules and enzyme inhibitors. This article deals with physicochemical properties of sulfonamides, synthesis of aminoalkylsulfonates and sulfonamidopeptides, and the biological activity of these compounds