Current Medicinal Chemistry - Volume 15, Issue 24, 2008

One of the most exciting scientific frontiers today is that of neurosciences. There is a growing interest in understanding some of the underlying chemistry which can influence the functioning of the human brain, particularly the chemical changes responsible for neurological and mental diseases such as epilepsy, Alzheimer, schizophrenia and depression. Exciting recent developments in proteomics and genomics promise to provide answers to many questions in this field, specially through the application of computational neuroscience and bioinformatics. The molecular basis of human memory i.e. identification of the precise molecular mechanisms for thought storage and recall remains a mystery. A theory based on the freezing of the conformational mobility of glycoproteins in the brain hippocampus by hydrogen bonding between the hydroxyl groups in glycoproteins offers a possible answer and may provide insights to some neural disease processes[1]. The present issue is largely focused on certain important aspects of neuroscience. The first article by Copani and coworkers discusses the mechanisms involved in neuronal apoptosis associated with Alzheimer's disease (AD), and drug development based on this hypothesis. The second review by Munoz-Torrero is concerned with the potential of acetylcholinesterase inhibition (ACHEIs) for use in AD. There is growing evidence of the key role of the ß-amyloid peptide (Aß) in the pathogenesis of AD, and the review discusses certain classes of ACHEIs which target Aß aggregation and/or other biological targets and which are promising anti-Alzheimer drug candidates. The third review by Ascoli and coworkers provides an insight of neuro-molecular medicine from the computational perspective. It describes how simulations can be used to study certain aspects of chemical agonists, antagonists and modulators in the nervous system. The review by Serretti and coworkers is concerned with the genetic framework responsible for the proarrhythmic effects of antidepressants and antipsychotics. These proarrhythmic cardiac side effects may be due to the interference caused by antidepressants and antipsychotics with certain ion channels which regulate the depolarization and repolarisation of cardiac myocytes. The review by Capasso discusses the role of prostaglandins (PGs) and nitric oxide (NO) in the development of brain excitability. Danese and coworkers have reviewed studies carried out on the mechanism of action, safety and efficacy of budesonide in the treatment of inflammatory bowel disease. It is hoped that these excellent reviews written by leading authorities in the field, who are all members of the Editorial Board of Current Medicinal Chemistry, will prove to be of wide interest to researchers in these fields. From 2009 onwards the journal will be publishing 36 issues based on reviews focusing on structure activity relationship analyses, technologies in inhibiting certain targets, mechanism of action, synthesis and biological properties of new agents and new targets of potential therapeutic intervention, and pharmacokinetic/pharmacodynamic relationships. The journal has become one of the top journals in the field of medicinal chemistry since it was founded 15 years ago. I would like to thank the Editorial & Advisory Board Members for their continual support by contributing high quality reviews and refereeing papers for the journal. Efforts of the hard working and enthusiastic editorial staff particularly Ms. Afshan Siddiq and Mr. Muhammad Faisal Shahab, are gratefully acknowledged.

Alzheimer's disease (AD), the leading cause of senile dementia, has become a considerable social and economical problem. Current AD therapeutics provide mainly symptomatic short-term benefit, rather than targeting disease mechanisms. The hallmarks for AD are ß-amyloid plaques, neurofibrillary tangles, and regionalized neuronal loss. Additional neuropathological features have been described that may provide some clues to the mechanism by which neurons die in AD. Specifically, the aberrant expression of cell cycle proteins and the presence of de novo-replicated DNA in neurons have been described both in AD brain and in culture models of the disease. The unscheduled cell cycle events are deleterious to neurons, which undergo death rather than complete the cell cycle. Although our understanding of the neuronal cell cycle is not complete, experimental evidence suggests that compounds able of arresting the aberrant cell cycle will yield neuroprotection. This review focuses on drug development centered on the cell cycle hypothesis of AD.

The therapeutic arsenal for the treatment of Alzheimer's disease (AD) remains confined to a group of four inhibitors of AChE and one NMDA receptor antagonist, which are used to provide a relief of the very late symptoms of the dementia, i.e. the cognitive and functional decline. In line with the growing body of evidence of the pivotal role of the β-amyloid peptide (Aβ) in the pathogenesis of AD, alternative classes of drugs targeting mainly the formation or the aggregation of Aβ are actively pursued by the pharmaceutical industry, as they could positively modify the course of AD, stopping or slowing down disease progression. While the first amyloid-directed disease-modifying drugs go ahead with their clinical development and could reach the market as soon as 2009, mounting preclinical and clinical evidences is pointing towards a disease-modifying role also for currently marketed anti-Alzheimer AChE inhibitors (AChEIs), particularly for donepezil. In this review, the neuroprotective effects exhibited by currently commercialized AChEIs will be briefly discussed, together with the secondary mechanisms through which they could exert such effects. This review will focus also on particular classes of AChEIs, namely dual binding site AChEIs, which are being purposely designed to target Aβ aggregation and / or other biological targets that contribute to AD pathogenesis, thus constituting very promising diseasemodifying anti-Alzheimer drug candidates.

The identification and characterization of potential pharmacological targets in neurology and psychiatry is a fundamental problem at the intersection between medicinal chemistry and the neurosciences. Exciting new techniques in proteomics and genomics have fostered rapid progress, opening numerous questions as to the functional consequences of ligand binding at the systems level. Psycho- and neuro-active drugs typically work in nerve cells by affecting one or more aspects of electrophysiological activity. Thus, an integrated understanding of neuropharmacological agents requires bridging the gap between their molecular mechanisms and the biophysical determinants of neuronal function. Computational neuroscience and bioinformatics can play a major role in this functional connection. Robust quantitative models exist describing all major active membrane properties under endogenous and exogenous chemical control. These include voltage-dependent ionic channels (sodium, potassium, calcium, etc.), synaptic receptor channels (e.g. glutamatergic, GABAergic, cholinergic), and G protein coupled signaling pathways (protein kinases, phosphatases, and other enzymatic cascades). This brief review of neuromolecular medicine from the computational perspective provides compelling examples of how simulations can elucidate, explain, and predict the effect of chemical agonists, antagonists, and modulators in the nervous system.

Antidepressants and antipsychotics may affect several ion channels involved in the control of cardiac action potential and be proarrhythmic. In this field, accurate understanding of genetics, which per se is a non-controllable risk factor, may help clinicians to prevent life-threatening side effects. So far, a number of genes have been associated with arrhythmia: SCN5A, SCN4B, CACNL1AC, KCNH2, KCNQ1, KCNE1, ANK2, ALG10, KCNJ2, KCNE2, RYR2, KCND3, KCND2, ACE, NOS1AP, CASQ2 and Rad. These genes represent good candidates for the definition of a genetic pro-arrhythmic profile. A genetic analysis of these targets is provided and their possible pathophysiological role in arrhythmias is discussed. Special attention is devoted to the interactions between these genes and new generation antidepressants and antipsychotics. A list of relevant rare mutations within the selected genes is presented, together with a complete list of Tag SNPs covering the whole genetic sequence. The aim of this paper is to define a part of the genetic framework responsible for the proarrhythmic effects of antidepressants and antipsychotics. The selected variants, both mutations and polymorphisms, may help in defining a next-to-come genetic assessment to be performed before drug prescription in order to improve drug safety.

The possible role of PGs and NO in the development of S&W of DBA/2J mice was investigated by evaluating the effects of dexamethasone, indometacin, mifepristone plus dexamethasone on the S&W, as well as of L-NAME both on the S&W in the electrocorticogram of DBA/2J mice and on morphine- and deltorphin II-induced EEG seizure in rabbits. The results of our data indicate that: a) Both dexamethasone and indometacin (1,10,100 μg/kg/i.p.) reduced the S&W of DBA/2J mice and mifepristone, a glucocorticoid receptor antagonist (1,10,100 μg/kg/i.p.), totally blocked the steroid effect b) L-NAME (3-300 μg/mouse/ i.c.v.) dose-dependently reduced the S&W of DBA/2J mice whereas DNAME at the same doses did not affect S&W of mice. The inhibitory effect of L-NAME on S&W of mice was dose-dependently reversed by L-arginine (L-ARG, 3-300 μg/mouse/ i.c.v.) but not by D-arginine. Finally, GTN its own (3-300 μg/mouse/ i.c.v.) significantly increased the S&W of mice and it was also able to reverse the inhibition on S&W of mice operated by L-NAME. c) Morphine and deltorphin II (100 μg/icv/toto) produce EEG seizure activity in rabbits and L-NAME (300 μg/i.c.v./toto), injected 15 min before morphine or deltorphin II, dose dependently prevented the EEG ictal episodes, the spiking activity and the synchronized EEG pattern induced by morphine or deltorphin II. The inhibitory effect of L-NAME on morphine or deltorphin II seizures was dose-dependently reversed by L-arginine (300 μg/icv/toto) but not by D-arginine. Finally, GTN on its own (300 μg/icv/toto) significantly increased morphine or deltorphin II seizures in the rabbit and it was also able to reverse the inhibition on morphine or deltorphin II seizures operated by L-NAME. These results provide a strong evidence that both PGs and NO may play a significant role in the development of brain excitability.

Crohn's disease and ulcerative colitis are chronic relapsing inflammatory bowel diseases with extremely great variability in presentation and clinical course. For many decades, corticosteroids and aminosalicylates have been the mainstay of the treatment for both Crohn's disease and ulcerative colitis, for the induction and maintenance of remission, respectively. The main limiting factors for the repeated use of corticosteroids or the use as a maintenance treatment are the very high prevalence of systemic side effects, together with the possibility of developing dependency on and/or resistance to the drug, which are reported in more than one third of patients with inflammatory bowel disease. In the last decade, a number of corticosteroids with enhanced topical activity and low systemic activity have been developed. Among them, budesonide and beclomethasone dipropionate are the most used for the treatment of the inflammatory bowel diseases. Indeed, budesonide is the drug of choice for the treatment of ileo(-cecal) active Crohn's disease with mild-to-moderate activity, due to controlled ileal release. Budesonide foam and/or enemas are also efficacious in the treatment of left-sided/distal ulcerative colitis. Gastroresistant, extended release tablets characterized by a multimatrix structure (i.e. MMX®-budesonide), have also been developed to allow uniform release along the length of the colon. This paper reviews the mechanism-of-action, safety and efficacy of budesonide in the treatment of inflammatory bowel disease.