Current Medicinal Chemistry - Volume 10, Issue 19, 2003

Modern neurology is becoming daily more complex and the practising physician finds it difficult to know the significance of particular advances in neurochemistry, neuroimmunology and molecular biology of the brain. In this special edition, we have brought together a number of learned scientists who have looked at common everyday neurological problems and given us insights as to how to look anew at the pathophysiology of these diseases and to institute effective treatment. We are certain that these papers will be timely and pertinent for the clinician and be of help to him both on the wards and in the clinic. We are sad to relate that one of the designated contributors to this special edition, Dr David Horrobin, has died. David was a unique man in many ways as true friend, physician scientist and colleague. It is a truism to say that one always felt better after meeting him where, with his unique infectious enthusiasm, jovial and kind spirit, he would always impart new knowledge in a novel way of looking at a difficult scientific problem. We dedicate this issue to his memory.

Coenzyme Q10 (ubiquinone), which serves as the electron acceptor for complexes I and II of the mitochondrial electron transport chain and also acts as an antioxidant, has the potential to be a beneficial agent in neurodegenerative diseases in which there is impaired mitochondrial function and / or excessive oxidative damage. Substantial data have accumulated to implicate these processes in the pathogenesis in certain neurodegenerative disorders, including Parkinson's disease, Huntington's disease and Friedreich's ataxia. Although no study to date has unequivocally demonstrated that coenzyme Q10 can slow the progression of a neurodegenerative disease, recent clinical trials in these three disorders suggest that supplemental coenzyme Q10 can slow the functional decline in these disorders, particularly Parkinson's disease.

Individuals with elevated homocysteine levels are at increased risk for cardiovascular disease and stroke, and neurodegenerative disorders such as Alzheimer's and Parkinson's diseases Homocysteine is a modified form of the amino acid methionine that is tightly regulated by enzymes requiring folate. By impairing DNA repair mechanisms and inducing oxidative stress, homocysteine can cause the dysfunction or death of cells in the cardiovascular and nervous systems. Dietary folate stimulates homocysteine removal and may thereby protect cells against disease processes. The enzymes involved in homocysteine and folate metabolism provide novel targets for drug discovery.

The balance between cytokines with pro- and anti-inflammatory effects contributes to the course of the Guillain-Barre syndrome and chronic inflammatory demyelinating polyneuropathy. TNFα seems to be an important factor in the cascade of events leading to demyelination and even axonal damage. During the acute phase, the serum concentrations of TNFα and IL-6 are elevated while anti-inflammatory cytokines are upregulated in the recovery phase. Cytokines also have a key role in the pathogenesis of multiple sclerosis and most data suggest that this effect is mediated by myelin-specific CD4 T lymphocytes secreting Th type 1 cytokines. However, several different immune cells including B lymphocytes, CD8 T lymphocytes and NK T lymphocytes are also involved in the pathogenesis. Both Th1 and Th2 lymphocytes and cytokines probably participate in the development of myasthenia gravis (MG). The IFNα production is probably related to the severity of the disease, with clinical improvement associated with decreased production. The serum levels of IL-18 are significantly elevated in MG, with highest concentrations in patients with generalized disease. The immune system may be involved in the pathogenesis of AD by the effect of microglia, which can induce microglial activation with subsequent release of pro-inflammatory cytokines. In parkinsonism, there is evidence of chronic inflammation in the substantia nigra and striatum. Activated microglia, producing proinflammatory cytokines, surround the degenerating dopaminergic neurons and may contribute to the dopaminergic neuron loss. Studies of patients with epilepsy and animals with experimentally induced seizures indicate that cytokines may also influence the electrophysiological properties of neurons.

Hashimoto's encephalopathy may present with a wide variety of different neurological symptoms and signs. These include recurrent severe migrainous headache, psychoses, seizures, ataxia, dementia, stupor and coma. We present a personal series of 18 adult patients with Hashimoto's encephalopathy and a review of the literature in this paper. The natural history, laboratory abnormalities and neuroimaging data in these cases favour an immunopathological basis for this syndrome similar to relapsing acute disseminated encephalomyelitis. We suggest that Hashimoto's encephalomyelitis should be considered in the differential diagnosis of seizures, coma, atypical migraine and reversible dementia. Serological screening for anti-thyroid antibody should form part of the initial investigations in all relapsing and reversible encephalopathies.

Viral infections have been associated with the development of several neurological and neuroendocrine autoimmune diseases. Structural similarities between environmental proteins and self-proteins have long been proposed to be targets for immune cross reactivity associated with initiation of autoimmune diseases. This mechanism called molecular mimicry has also been put forward for immune mediated neurological diseases associated with viral infection. Although many potential candidates for cross reactivity have been put forward, only few have been substantiated on the molecular level. For the definition of cellular immune cross-reactivity, it proved critical to appreciate that recognition patterns of T-cells are not linear. Subsequent microarray studies unequivocally demonstrated functional mimicry of seemingly disparate amino acid sequences. This review summarises the present evidence for molecular mimicry in neurological autoimmune diseases and virus.

This review represents a compilation of typical substrates and inhibitors for human cytochrome P450 (CYP) enzymes that are involved in drug metabolism, specifically those from the CYP1, CYP2 and CYP3 families. Relatively recent literature on substrates and inhibitors has been collected and the relevant Km and Ki values, respectively, are tabulated. Furthermore, physicochemical properties in the form of lipophilicity (log P and log D7.4 values) and acidity / basicity (pKa values) are also tabulated for a significant number of substrates, together with some information on inhibitors, although only key inhibitors have been selected as the main focus is on substrates. The collated information indicates that there are certain commonalities between substrates for the same enzyme, especially with respect to their positions of metabolism and likely interactions with the relevant enzyme active site regions. The compilation therefore assists in establishing substrate structure-activity relationships (SSARs) within human drug-metabolizing P450s.

In recent years modified oligonucleotides (oligos) have become an area of increased research activity. These synthetic biopolymers have long been used as molecular probes to understand better the interaction between proteins and nucleic acids at molecular level, which in fact is responsible for all aspects of cellular or viral gene expression. Modified oligos have also been used as therapeutic and diagnostic agents. For example, the antisense oligos are used to block gene expression by binding especially with complimentary sequences of target mRNA. Also, over the past decade efforts are made to modify the native phosphodiester linkages to improve nuclease resistance and membrane permeation of naturally occurring oligonucleotide for therapeutic applications. Therefore, design and synthesis of modified oligonucleotides for a wide range of applications are of interest for bioorganic chemists and biologists. The advent of the phosphoramidite chemistry has accelerated the development of oligos with modified nucleobases, phosphate-protecting groups and modified sugars. In this review, we have presented the recently reported nucleoside based phosphoramidites with modified base, sugar or backbone units and their subsequent conversion into modified DNA and RNA analogs. The effect of such modification on structural, thermodynamic, and hybridization properties of the modified oligos and their duplex with natural complementary oligos have also been discussed for some cases. Similarly, we have highlighted the role of modified nucleoside phosphoramidite building blocks in synthesis of oligos modified with optically or electrochemically active molecules. Nucleoside phosphoramidites or small oligos immobilized over solid supports through different linkages or groups and their biological applications has also been mentioned.

Glycosaminoglycans, highly charged polycarboxylated, polysulfated polysaccharides, are an important class of therapeutic agents and investigational drug candidates. Heparin has been widely used as a clinical anticoagulant for over 60 years. Low molecular weight heparins have begun to displace heparin and recently a synthetic heparin pentasaccharide was approved for clinical use in Europe. In addition to heparin (and the related heparan sulfate glycosaminoglycan), dermatan sulfate, chondroitin sulfate, hyaluronan and their derivatives are all in various stages of clinical evaluation. This review focuses on the chemical and chemoenzymatic synthesis of glycosaminoglycan oligosaccharides. Recent advances in functional group protection chemistry, conversion of D-gluco to L-ido or D-galacto configurations, glycosylation reactions and the preparation and use of novel starting materials in acidic oligosaccharide synthesis are discussed.

From the synthetic point of view the fast developing fields of medicine and biology offer new opportunities for the design of very effective drugs with high selectivity. Especially in the field of anticancer therapy many efforts have been made to deliver drugs to specific tissues. Sugar substituted porphyrin compounds, bile acid conjugates, and pH-sensitive immunoliposomes are only some examples. Although there are many different approaches to exploit biomolecules as shuttles only a start has been made. Since the targeting of a drug is a very complex process, a successful design of a new compound has to consider chemical as well as biological aspects and requires a multidisciplinary cooperation with physicians and biologists. Three interesting concepts are evaluated exemplarily: antibodies, molecules with binding affinity to hormone receptors, and bile acids. The main issues are: selection of the drug and the carrier, ways of linking the pharmacological active compound to the biomolecule, the optimal way of linking the drug to the spacer, and cytotoxicity, apoptosis, and drug resistance.

Gap junctions are unique intercellular channels that connect the cytoplasm of adjacent cells. They are the only channels that mediate the direct cytoplasmic exchange of small hydrophilic molecules between cells - a process called gap junctional communication. Formed by a family of integral membrane proteins called connexins, gap junctions are dynamic multifunctional complexes that are essential for healthy vertebrate development and physiology. Defects in connexin proteins, and, therefore, in gap junctional communication, are associated with a large variety of pathologies in humans and experimental animals. Thus, knowledge of the molecules that pass through gap junction channels is extremely important. However, aside from some notable cases, the repertoire of biologically important transjunctional molecules remains relatively unexplored. Indeed, the study of the intercellular transfer of endogenous molecules presents formidable challenges. Here we review developments in identifying biologically relevant molecules that pass between cells through gap junction channels.