Current Medicinal Chemistry - Volume 16, Issue 26, 2009

Calcium-Channel Blockers (CCBs), or calcium antagonists, are a heterogeneous group of drugs that produce cardiovascular effects by preventing the influx of calcium ions through L-type voltage-dependent calcium channels in specialized electrical system and conduction tissue cells, like myocardial and vascular smooth muscle cells. In recent years, CCBs have found their way in obstetrics and gynecology, especially in the management of hypertensive disorders of pregnancy and preterm labor. The lack of adequate data had created uncertainty about the safety of CCBs in pregnancy. Teratogenicity with these agents has been demonstrated in animals, but no cases of possible human malformation or deformity have been reported. Data from human studies suggest that CCBs may cause a clinically insignificant fall in maternal mean arterial pressure, but have little to no effect on uterine perfusion. In many countries, CCBs remain unlicensed for use in pregnancy and it is unlikely the manufacturers will ever apply for this status to change. We do believe that this is the situation of CCBs for those critical second- and third-trimester conditions such as Gestational hypertension, Preeclampsia, HELLP syndrome and preterm labor.

The L-type Ca2+ channel plays a critical role in cardiac function as the main route for entry of calcium into cardiac myocytes. It is essential to excitability as it shapes the long plateau phase of the cardiac action potential that is unique to cardiac ventricular myocytes. It is necessary for contraction as it triggers the release of calcium from sarcoplasmic reticulum stores for actin-myosin interaction. The L-type Ca2+ channel also regulates cytoplasmic calcium levels. It is well recognized that an increase in intracellular calcium is involved in the activation of growth-promoting signal pathways. Recently, reactive oxygen species have been implicated in the activation of signal pathways and the development of pathological hypertrophy. There is now evidence that implicates activation of the L-type Ca2+ channel with persistent alterations in calcium homeostasis and cellular reactive oxygen species production as a possible trigger of cardiac hypertrophy. A number of different approaches have been used to modify channel function with the view to preventing ischemiareperfusion injury, cardiac hypertrophy or cardiac failure providing good evidence that the L-type Ca2+ channel may be an efficacious target in the prevention of cardiac pathology.

The Translocator protein (TSPO), formerly known as the peripheral-type benzodiazepine receptor, is an 18 kDa mitochondrial protein primarily involved in steroid biosynthesis in both peripheral and glial cells. It has been extensively reported that TSPO regulates the rate-limiting translocation of cholesterol from the outer to the inner mitochondrial membrane before its transformation by cytochrome P450scc into pregnenolone, which is further converted into an array of different steroids. In the brain, neurosteroids such as allopregnanolone and pregnenolone, acting as positive modulators of γ-aminobutyric type A (GABAA) receptors, exert anxiolytic activity. Specific ligands targeting TSPO increase neurosteroid production and for this reason they have been suggested to play an important role in anxiety modulation. Unlike benzodiazepines (Bzs), which represent the most common anti-anxiety drugs administered around the world, selective TSPO ligands have shown anxiolytic effects in animal models without any of the side effects associated with Bzs. Therefore, specific TSPO ligands that are able to promote neurosteroidogenesis may represent the future of therapeutic treatment of anxiety disorders. Furthermore, TSPO expression levels are altered in several different psychiatric disorders in which anxiety is the main symptom. This article reviews the primary and patent literature over the last decade concerning the development of novel TSPO ligands that have resulted effective in various models of anxiety, taking into special consideration their structure-activity relationships.

The pharmacological properties of small organic molecules depend on their three-dimensional (3D) structure. That includes physico-chemical properties (e.g. solubility, partition equilibria) and molecular recognition such as binding to a therapeutic macromolecular target. At physiological temperature, the 3D structure of a flexible small molecules is expected to cover an ensemble of energetically accessible conformations. Therefore, it is of fundamental and practical importance to be able to relate the energetics of a molecule to its conformational preferences and derived properties, a discipline known as conformational analysis. The first step of conformational analysis is the generation of the conformers, referred to as conformational sampling. This is typically performed primarily using computational chemistry methods. Taking a fresh look at these methods for a broad medicinal chemistry audience is the object of the present review. Indeed, conformational sampling methods continue to be developed, improved and tested. They underpin much of the detailed analysis of structure-activity relationships on selected chemical series, but also the preparation of large conformational libraries of generic compounds and their exploitation for virtual screening. In recent years, the conformational models of active compounds have been examined to see how frequently they capture their target-bound bioactive conformation, as revealed by X-ray crystallography. This provided a context to scrutinize the intrinsic conformational energetics of these bioactive conformers, and this subject is still intensely debated. Another line of investigation concerns the conformational diversity of the 3D models, and how well they cover the conformational and pharmacophoric spaces. This review addresses in general terms: i) the basic principles of conformational analysis, including modern computational estimates of intramolecular energy and how those are mapped on the molecular potential energy surface, ii) some experimental contributions to probing of the small molecule conformations, iii) the various computational methods available to generate conformational models, iv) the conformational properties of the bioactive conformers, and v) attempts to quantify the coverage of the conformational models and the controlling parameters.

In contrast with the parent class of flavonoids, the distribution of the isoflavonoid class in the plant kingdom is relatively limited, probably owing to the sporadic occurrence of isoflavone synthase. Isoflavonoids have been mostly found in the subfamily Fabaceae/Papilionoideae of the Leguminosae family. Isoprenoid-substituted (also called complex) isoflavonoids are expressed from a smaller number of plants, as a result of the similarly restricted distribution of prenyltransferases (PT-ase). After the reviews of Tanara & Ibrahim (1995), Boland & Donnelly (1997), the Handbook of Flavonoids by Harborne & C (Handbook of Flavonoids, 1999), and the paper by Harborne and Williams (2000) few other reports concern the distribution and the biological activity of complex isoflavonoids, except a list of isoflavonoids produced from non leguminous plants. This review deals with an update of the literature on isoprenylated isoflavonoids in the years 1995-2006 and is focused on the following highlights. 1. Natural sources of complex isoflavonoids (2000-2006) 2. Chemical structure variety: new entries (2000-2006) 3. Biological activities and a possible structure-activity relationship (1995-2006) 4. In vitro production and microbial metabolism (1995-2006)