Drug Design Reviews - Online (Discontinued) - Volume 2, Issue 4, 2005

Activation of the central sympathetic nervous system has proved to be a definitive pathophysiological feature in cardiovascular diseases such as primary arterial hypertension, heart failure and arrhythmogenesis during myocardial ischemia. In fact, experimental and clinical evidence suggests sudden cardiac death in ischemic patients to be, at least in part, mediated by the central sympathetic nervous system. In addition to the use of peripherally acting sympatholytic agents, sympathetic overactivity can also be modulated by drugs acting directly on its site of origin, i.e. the central nervous system. In this context, clonidine, a centrally acting antihypertensive drug that displays alpha2-adrenergic agonistic properties, has long been used in the protection of the ischemic heart during surgery in patients with coronary artery disease. Using an experimental model associating central sympathetic overactivity with myocardial ischemia in rabbits, we demonstrated that clonidine and rilmenidine present protective effects of central origin against ventricular arrhythmia, myocardial ischemia and sudden death. Moreover, the protective effects of rilmenidine, a second-generation antihypertensive drug devoid of significant sedative effects, can also be obtained at subhypotensive doses. Finally, we investigated the central cardioprotective effects resulting from the activation of the opioid receptors in the above mentioned experimental model. We showed that clinically relevant doses of fentanyl, an opioid agonist widely used in anesthetic procedures, also elicited significant cardioprotective effects. Clinically, these results are relevant because they confirm the usefulness of opioids in the prevention of arrhythmia and myocardial ischemia in the perioperative period in patients with coronary artery disease. In conclusion, inhibition of central sympathetic overactivity in patients presenting with coronary artery disease emerges as an attractive pharmacological target to the development of cardioprotective drugs.

The clinical use of doxorubicin and other anticancer anthracyclines is limited by the possible development of a life-threatening form of cardiomyopathy. Here, we briefly review biochemical and pharmacological studies that identify secondary alcohol metabolites as important mediators of cardiotoxicity induced by anthracyclines. The pharmacokinetics and pharmacodynamics of secondary alcohol metabolites suggest that they might cause cardiotoxicity while not mediating or actually diminishing the antitumour potency of anthracyclines. This concept implies that novel anthracyclines forming fewer amounts of their secondary alcohol metabolites might prove to spare the vulnerable cardiomyocytes while also retaining good activity in cancer cells, thus offering advantages over currently available anthracyclines in terms of therapeutic index. MEN 10755 (sabarubicin) is a newly designed disaccharide anthracycline that fits well in this context: it forms less alcohol metabolite than doxorubicin, and consistently induces less cardiac toxicity in laboratory animals in the face of an equal or even improved spectrum of activity in human tumour xenografts. On the basis of these preclinical findings, MEN 10755 has entered clinical trials, which will define its activity and safety and will serve an opportunity to probe the "secondary alcohol metabolite hypothesis" of cardiotoxicity.

Opioids acting through the μ opioid receptor traditionally represent the most effective analgesic agents. Alternatively, ligands acting as agonists at theδopioid receptor have been pursued as analgesic agents lacking the undesirable effects of m opioid agonists including morphine. This interest led to the development of selective peptide and non-peptideδligands, contributing to a better understanding of the physiological role of theδopioid receptor, including its interaction with other receptor systems. It is now understood that theδopioid receptors are involved in other biological processes, thereby providing tremendous therapeutic potential for agents acting at theδreceptor. Computer-aided modeling studies, in conjunction with pharmacological investigations of theδligands, have the potential to facilitate the exploitation of this potential via the development of predictive structure-activity relationships (SAR). To date, modeling studies have been performed on both peptidic and non-peptidicδligands, including conformational studies of constrained ligands, facilitating the identification of bioactive conformations ofδligands. In the present article, an overview of these modeling studies will be presented, with emphasis on the long-term goal of the development of therapeutic agents acting on theδopioid receptor.

Diabetes mellitus exacts a huge toll in money and human suffering. At its present rate of increase, within few decades it will be one of the world's commonest diseases and biggest public-health problem, with an estimated minimum of half-a-billion cases. The diabetic individual is prone to late onset complications that are largely responsible for the morbidity and mortality observed in the patients. It has been demonstrated that the more severe and sustained the degree of hyperglycaemia, the more likely it is that the chronic complications of diabetes will develop. Pharmaceutical intervention of hyperglycaemia-induced diabetic complications is actively pursued since it is very difficult to maintain normoglycaemia by any means in patients with diabetes mellitus. Aldose reductase enzyme (AR, ALR2, E.C. 1.1.1.21) of the polyol metabolic pathway was first found to be implicated in the aetiology of secondary complications of diabetes. AR inhibitors (ARIs) have therefore been noted as possible pharmacotherapeutic agents. Although several ARIs have progressed to the clinical level, only one is currently on the market. However, the inhibition of the polyol pathway is considered to be a promising approach to control diabetes complications as well as a number of other pathological conditions like ischemia, abnormal vascular smooth muscle cell proliferation, cancers, and mood disorders. Thus, attention is currently targeted to discover ARIs of distinct chemical structures, being derivatives of neither hydantoin nor carboxylic acid, which are known to cause either toxicity, or posses narrow spectrum of tissue activity. Glucose and, especially, fructose can react with proteins to form alpha keto-amines via Amadori rearrangements. This can lead, through Maillard type reactions, to advanced glycation end products (AGEs) and damage of proteins. Glucose and fructose can undergo transition metal catalyzed oxidations, which contribute to acceleration of modifications in the tissues. AGEs thus formed by the above mentioned non-enzymatic reactions between monosaccharides and proteins, have been implicated as a major pathogenesis process leading, for example, to diabetic complications, atherosclerosis, Alzheimer's disease and Creutzfeldt-Jakob disease. In the present review, the data that will be presented will aim to support the notion that compounds which combine aldose reductase inhibitory activity and ability to prevent the glycation of proteins posses' pharmacotherapeutic potential.

Leucine-rich repeat (LRR)-containing proteins are present in over 4700 proteins from viruses to eukaryotes. Many LRR proteins are involved in protein, ligand interactions; these include plant immune response and the mammalian innate immune response. This review describes the present status of our understanding of their structures, functions, evolution and interactions with ligands. Most LRRs are 20 to 30 amino acids long and the repeat number ranges from 2 to 52. The LRR proteins have been divided into seven classes. One group of proteins has LRRs from more than one of the seven classes. The subfamily of small leucine-rich repeat proteoglycans and its related proteins including FLRT, ECM2, oligodendrocyte-myelin and glycoprotein, and Slit have two types of LRRs (S and T). These S and T LRRs are ordered into two super-motifs - STT and ST. A probable pattern of evolution of the SLRP and its related proteins was proposed based on the super-motifs. The known structures of the LRR proteins have revealed that the LRR domains fold into an arc shape with a parallel β-sheet on the concave face and with various secondary structures including the α-helix, 3 10-helix, and polyproline II helix on the convex face. Four geometric parameters, the radius (R) of the LRR arc, its mean rotation angle (φ), the tilt angle of β-strand direction per turn (θt), and the mean twist angle of b-sheets (|τ|) were estimated. These parameters well characterize all the LRR arcs. Most of the known LRR structures have a cap, which shields the hydrophobic core of the N-terminal LRR or the C-terminal LRR. The concave surfaces of the arcs frequently interact with ligands. Interactions on the concave surfaces induce an increase in R and θt. There is growing evidence of striking similarities between the molecular organization of both animal and plant systems for non-self recognition and antimicrobial defense.

Graphical Abstract: Nucleic-acid-based gene silencing molecules, including antisense oligodeoxyribonucleotides, ribozymes, DNAzymes and small interfering RNA, have been discussed on their mechanisms of action and potential applications in antiviral therapy. The sequencing of many human viral genomes and the elucidation of molecular mechanisms of viral replication as well as signal transduction pathways involved in viral pathogenesis have provided unprecedented opportunities for the development of new therapeutics. One type of the most promising molecules in drug development is the nucleic-acid-based therapeutics, including antisense oligodeoxyribonucleotides (AODN), ribozymes, DNAzyme and small interfering RNA (siRNA). AODNs have shown great potential as powerful tools in gene functional studies, as well as highly selective therapeutic agents in drug development. Although several problems have been encountered such as toxicity, non-stability, side effects, and low intracellular uptake, there has been at least one antisense drug approved for the treatment of cytomegalovirus retinitis, and over twenty other antisense candidates are undergoing clinical trials. Ribozymes and DNAzymes, by binding to substrate RNA through base pairing, offer sequence-specific cleavage of disease-associated RNA transcripts and show great potential for development of novel antiviral agents. RNA interference has emerged as a novel tool that offers great hope and promise to study gene functions and to develop therapeutics against viral infection. This powerful antiviral effect is mediated by siRNAs that target the viral mRNA for degradation by cellular enzymes. The potential of siRNA to treat or prevent diseases in clinical settings remains to be proven. This article first overviews current nucleic acid-based approaches in gene silencing, and then focuses on the potential applications in antiviral therapy including our own data on coxsackieviral infection.

The chronic painful tendon is well known to be difficult to treat, and the source of pain has not been scientifically clarified. For chronic painful conditions in the Achilles-, patellar-, and ECRB tendons there is no treatment of choice, but a huge variety of proposed treatment regimens. There is sparse scientific evidence for most of the conservative and surgical treatments proposed and used. Recent research, using ultrasonography (US) together with colour Doppler (CD), and immunohistochemical analyses of biopsies, has demonstrated a vasculo-neural (SP- and CGRP-nerves) ingrowth in the area with structural tendon changes. Also, tendon pain was temporarily cured by US- and CD-guided injections of a local anaesthetic targeting the neovessels outside the tendon. A specially designed treatment were US- and CD-guided injections of the sclerosing agent Polidocanol (primarily acting on the intima layer in the vascular wall), aiming to destroy the neovessels and accompanying nerves, has in pilot studies cured the tendon pain in the majority of patients with chronic painful Achilles and patellar tendinosis. Follow-ups (> 2 years) showed remaining good clinical results, a significantly decreased tendon thickness, no remaining neovessels, and ultrasonographically a more normal tendon structure. The importance of using Polidocanol, was verified in a randomized double-blind study.