Medicinal Chemistry Reviews - Online (Discontinued) - Volume 2, Issue 1, 2005

Several antiresorptive agents have been developed for the treatment of osteoporosis and bone disorders. Few agents have been introduced that stimulate bone formation. Treatment with parathyroid hormone induces, however, a potent increase in hip and lumbar bone mineral density (BMD) and is now available in some countries. The present review focuses on growth hormone (GH) / GH secretagogues (GHSs). GH / GHSs stimulates bone turnover, thereby increasing bone mass and density.

The blood-brain barrier (BBB) represents a functional interface between the blood stream and the neuronal microenvironment. Distinct cellular and molecular features of brain microvessel endothelial cells result in barrier and carrier functions that guarantee exclusion of adverse components such as neurotoxic metabolites on the one hand and selective passage of essential nutrients on the other hand. The retina, as an integral part of the central nervous system, is enclosed by the pigment epithelium, which functions as a barrier interface between the systemic blood vessels of the neighboring choroid and the retina. Various BBB-specific markers, tight junction components, and carrier systems including amino acid- and saccharide transporters have been cloned and are expressed both in brain microvessels and the retinal pigment epithelium (RPE). P-glycoprotein has been of special interest because this efflux pump counteracts entry of numerous therapeutically relevant drugs into the nervous system. Various in vitro systems of the RPE have been established and employed to analyze pharmacological aspects and pathological cell interactions. The most advanced systems are organotypic cultures and acute preparations of the RPE, i.e. fully intact tissue sheets that can be used as in vivo-like BBB models for transport studies and drug profiling.

The metabotropic glutamate receptor (mGluR) system plays a critical role to foster the proper development of an organism. Yet, what has unfolded over the last decade is the vital interplay between the mGluR system and the fate of a cell during both acute and chronic neurodegenerative disorders. Through the coupling to guanosine-nucleotide-binding proteins, the mGluR system drives a series of cellular pathways that impact upon the apoptotic induction of genomic DNA fragmentation, membrane phosphatidylserine (PS) residue exposure, and the inflammatory activation of microglia in the brain. A broad array of cellular pathways appear to be governed by the mGluR system and include the protein kinases PKA, PKB, and PKC. In addition, distinct modulation of mitochondrial membrane potential, caspase activity, intracellular pH, and endonucleases are required to ultimately preserve the integrity of a cell. Cytoprotection by the mGluR system is clinically significant, since neuronal and vascular cell populations can benefit from immediate and delayed protection by mGluRs. Although mGluR activity may not always promote the survival of a cell and final outcome can be intimately linked to the environmental stimulus, future work with the mGluR system will guide the development of novel strategies to prevent cellular injury by this glutamate receptor family.

The inflammation in the airways of allergic patients is the result of a complex process involving several cytokines. Modulation of the effect of these cytokines can provide alternative and more specific treatment approach to currently widely used systemic immunosuppression by glucocorticoids. Theoretically, cytokine modulation can be achieved via several pathways, including inhibition of released cytokines by using antibodies or soluble receptors, blocking cytokine receptors, inhibiting signal transduction or preventing cytokine gene transcription. On the other hand, some cytokines are known to possess anti-inflammatory effects in allergic inflammation, being potentially used as a therapeutic agent. The more novel approaches for cytokine modulation include high affinity blockade of cytokines with cytokine traps and use of oligodeoxynucleotides for Th2 type cytokines. The current review addresses cytokine modulation as a strategy in targeting allergic diseases with emphasis on the clinical experience.

Both epidemiological and laboratory studies have suggested an inverse association between consumption of green tea and the prevalence of some cancers. The anti-tumorigenicity of green tea has been related to its content of specific polyphenols. The molecular mechanisms underlying the anticancer and antiangiogenic effects of green tea polyphenols (GTPs) are currently under intensive investigation. The purpose of this article is to update a previous review on the effects and biological activities of GTPs in relation to their therapeutic usefulness in preventing cancer in humans [1]. GTPs mainly consist of catechins (3-flavanols), of which epigallocatechin gallate (EGCG) is the most abundant in green tea and the most extensively studied. Moreover, the biological effects reported for GTPs have been mainly associated to EGCG. New perspectives on the applications of dietary GTPs as potential therapeutic and preventive agents against cancer are presented.

Although the aetiology of drug psychosis or schizophrenia is still unknown, molecular and biochemical researches have recently made significant advances in the search for the candidate genes of these disorders. Among such studies are animal models of drug psychosis or schizophrenia such as amphetamine-induced behavioural sensitisation or phencyclidine-treated animals. In this review, it is suggested that amphetamine or phencyclidine change the gene expressions related to cell damage / neuroplasticity. These alterable gene expressions may lead to the discovery for candidate genes of drug psychosis or schizophrenia and thus to novel antipsychotics.

Two recent lines of data open the way to development of subunit vaccines. It is now clearly established that ligands of TLR or signalling receptors of DCs could be used as potent adjuvants for vaccination purposes. In addition, it is possible to potentiate DNA vaccines by including cytokine genes.

Chemotherapy is currently the most important medical modality of treatment of cancer. Several studies have shown that most, if not all, chemotherapeutic agents exert their anticancer activity by inducing apoptosis (programmed cell death). Although successful treatment of some malignancies has been achieved, most of solid tumors are scarcely responsive to chemotherapeutic agents. The progress made in the area of apoptosis has led to the development of several apoptosis stimulators compounds for the control of cancer. A number of compounds able to activate directly apoptosis by acting on molecules involved in the apoptotic pathway, such as TRAIL receptor, caspases and the Bcl-2 family of proteins have been recently developed. Most are still in the preclinical study, but some have already shown promising results. Other recently developed anticancer drugs induce indirectly apoptosis by acting on targets different from that of classic chemotherapeutic drugs. Here, we review the experimental and clinical results of several promising pro-apoptotic anti-cancer compounds.

The most established nucleic acid based approach to gene suppression at the RNA level is through antisense oligodeoxynucleotides (ODNs). These compounds form heteroduplex with target RNA, which are thought to either block its function or mediate its destruction by activation of RNase H. Alternatively, RNA can be targeted by catalytic RNA such as the hammerhead ribozyme. Ribozymes have the advantage of being equipped with their own RNA cleavage apparatus, and are therefore independent of host nuclear protein activity. At present, the utility of ribozyme oligonucleotides is restricted by the relative difficulty in synthesising active molecules with sufficient resistance to nuclease degradation. Recently the power of in vitro selection has been used to evolve catalytic DNA sequences with RNA cleavage specificity and activity rivalling the very best ribozymes, while maintaining the more robust chemistry of an ODN. These deoxyribozymes or DNAzymes have tremendous potential as gene suppression agents for both target validation and therapeutic applications. A number of studies evaluating the biological activity of these compounds have shown promising results. However, as with other oligonucleotide-based strategies, future exploitation of this approach may depend on accessory technology to assist with the accessibility of a target, which is folded by its own secondary structure and hidden within the intracellular compartment.