Current Medicinal Chemistry - Volume 9, Issue 15, 2002

The peripheral benzodiazepine receptors (PBRs) have been identified to bind selectively benzodiazepine ligands and an isoquinoline carboxamide derivative PK 11195 with high affinity. PBRs are present in the central nervous system (CNS), peripheral tissues, and most organs in the human body. PBRs are different from the central benzodiazepine receptors (CBRs) related to the nerve cell membrane GABAA receptor and are thought to play several physiological and pathophysiological functions in the CNS and immune system due to their meanly localization in glial cells, the mitochondrial outer membrane of peripheral cells and blood leucocytes and to their important roles in steroidogenesis, cell proliferation and differentiation. Recent research has shown that the density of PBRs is significanly increased in CNS several disorders, such as epilepsy, multiple sclerosis, cerebral ischemia, astrocytoma, brain injury and neurodegenerative diseases.Recent progress in the pharmacology of PBRs is reviewed here with respect to the functions in the brain and peripheral tissues including apoptosis, immune system modulation, seizure promotion, reactions of anticonvulsants on peripheral blood cells, and adverse drug reactions (ADR) of anticonvulsants.

The branched-chain fatty acid valproic acid (VPA) is the most commonly used antiepileptic drug for treating generalized epilepsy. Although originally considered to be of low toxicity, VPA has proved to possess considerable teratogenic potential when applied to the pregnant epileptic women. During the last few years, it has become evident that some of the mechanisms which account for the malformations produced by VPA are related to distinct anti-tumor properties of this compound. This intriguing discovery opens novel aspects for the treatment of tumor patients. In the present review, the biological, biochemical and pharmacological properties of VPA are discussed. Analyses of structure-activity relationships can provide the necessary insight into the molecular structures responsible for the anti-tumor effects.

Malaria is the major parasitic infection in many tropical and subtropical regions, leading to more than one million deaths (principally young African children) out of 400 million cases each year (WHO world health report 2000). More than half of the world's population live in areas where they remain at risk of malaria infection. During last years, the situation has worsened in many ways, mainly due to malarial parasites becoming increasingly resistant to several antimalarial drugs. Furthermore, the control of malaria is becoming more complicated by the parallel spread of resistance of the mosquito vector to currently available insecticides. Discovering new drugs in this field is therefore a health priority. Several new molecules are under investigation. This review describes the classical treatments of malaria and the latest discoveries in antimalarial agents, especially artemisinin and its recent derivatives as well as the novel peroxidic compounds.

This review traces the origins of the chemical structure of the cyclooxygenase inhibitors celecoxib and rofecoxib. Early results from the search for non-steroid estrogens led to the triaryl-ethylenes such as chlortrianisene. A congener that incorporated a water-solubilizing basic ether grouping unexpectedly led to an estrogen antagonist and eventually the drug clomiphene. Elaboration of the structure gave the widely used drug used to treat breast cancer tamoxifen. Cyclized analogues such as nafoxidine showed equivalent activity but were not pursued. Later elaboration of those structures gave the now-marketed drug raloxifene. An indole analogue, indoxole, (2,3-dianisylindole) surprisingly showed anti-inflammatory activity. An analogue program designed to reduce photosensitivity from that compound eventually led to the discovery that the indole ring could be replaced by a simple thiazole, This resulted in the experimental cyclooxygenase inhibitor itazagrel. This compound incorporates many of the structural features found in celecoxib.

Human serum albumin (HSA) plays a fundamental role in the transport of drugs, metabolites, and endogenous ligands. Binding to HSA controls the free, active concentration of a drug, provides a reservoir for a long duration of action, and ultimately affects drug absorption, metabolism, distribution and excretion. The free concentration of a drug can also be affected by interaction with co-administered drugs or by pathological conditions that can modify to a significant extent the binding properties of the carrier, resulting in important clinical impacts for drugs that have a relatively narrow therapeutic index.This manuscript will review the physiological role of albumin in the human body and the pharmacological consequences of drug-albumin binding, and then focus on the structure and the properties of the protein binding sites, as studied by different methodologies. Among these, biochromatography on immobilized albumin has been shown to be a rapid and effective tool for the characterization of albumin binding sites and their enantioselectivity, and for the study of the changes in the binding properties of the protein arising by interaction between different ligands. We will discuss the potential offered by the combined use of circular dichroism on the same protein / drug system in solution, not only for the determination of binding parameters and the detection of displacement phenomena, but also for the identification of conformational features underlying binding stereoselectivity. In particular, the essential role of these methodologies in the study of the enantioselective phenomena occurring in the HSA binding of chiral drugs will be addressed. The effect of reversible or covalent binding of drugs will also be discussed and examples of physiological relevance reported.

The number of herbal formulae considered to be clinically effective and recorded in the Chinese medical literature is huge. The scientific basis for the remedial effects of these herbal formulae is not yet understood, nor has a clear need been given as to how to make use and combine traditional Chinese medicine (TCM) and Western medicine in an effective way. In this context, it is of interest to ascertain what individual constituents are responsible for the bioactive properties, and thus to extract the common characters of composition of huge formulae to provide a scientific explanation for their modes of action. We consider polyphenols and saponins as the key ingredients in TCM remedies responsible for most of the observed biological effects, reflecting the specific requirements within the TCM philosophy of treatment based on the investigation of its chemical composition.