Current Drug Targets - Volume 1, Issue 3, 2000

Calcium flow through the ion channel of the N-methyl-D-aspartate receptor (NMDAR) has been implicated as contributing to a variety of neuropathologies. This receptor is a complex heteromeric oligomer consisting of different types of subunits, the nature of which governs its properties, as well as its response to a variety of agonists, antagonists, and other types of inhibitors. A new natural series of NMDAR inhibitors, the conantokins, have been shown to be present in the venoms of snails within the genus, Conus. These agents appear to function by inhibition of the spermine/spermidine stimulation of ion flow through the NMDAR channel. These small peptides (17-27 amino acid residues) are highly processed post-translationally. One such processing event is the vitamin K-dependent gamma-carboxylation of glutamate, resulting in placement of gamma-carboxyglutamic acid residues in these peptides. As a result, these peptides then possess the ability to interact with divalent metal ions and concomitantly undergo a conformational alteration. Rational drug design based on the characteristics of these promising peptides requires knowledge of their properties and the manner in which they target the NMDAR. This review summarizes current knowledge in this area.

Phenothiazines and its related compounds have shown diverse biological activities including psychotropic, anticancer and other pharmacological activities. Recent studies have suggested the possible interactions between phenothiazines and their physiological targets or potential receptors. New types of phenothiazine, such as half-mustard type phenothiazines and benzo[a]phenothiazines, have been synthesized. These compounds stimulated T-cell blast formation, natural killer cell activity (possibly via activation of monocytes and macrophages) and antibody-dependent cellular cytotoxicity of human peripheral blood mononuclear cells, and showed cytotoxicity against several human cancer cell lines. Benzo[a]phenothiazines induced monocytic differentiation and apoptotic cell death (characterized by internucleosomal DNA fragmentation) in human myelogenous leukemic cell lines, but not in other cancer cell lines. These compounds also induced antimicrobial activity in vivo, possibly by host-mediated immunopotentiation. On the other hand, phenothiazines did not induce such immunopotentiation activity, but showed direct antibacterial activity in vitro. There was positive relation between their radical intensity and biological activities. These compounds did not show any apparent mutagenic activity, but rather be antimutagenic. These data suggest their possible applicability of half-mustard type phenothiazines and benzo[a]phenothiazines for cancer chemotherapy.

Erectile dysfunction (ED) is a common problem, particularly in older men. The production of penile erection involves an interplay between autonomic nerves and locally released vasoactive mediators. Endothelin-1 (ET-1) is a peptide released from endothelium in the corpus cavernosum, which causes smooth muscle contraction. Recent studies have investigated the physiological significance of ET-1 in the control of erectile function and it may play a role in detumescence. There is also much evidence to link ET-1 to risk factors for ED. ET-1 antagonists may prove beneficial in the treatment of ED and also in prevention of long term deterioration of erectile function. These antagonists may also find a role when used in combination with agents, which are established for the treatment of ED.

Over the last 30 years or so, the incidence of invasive fungal infections in man has risen dramatically. Patients that become severely immunocompromised because of underlying diseases such as leukemia or recently, acquired immunodeficiency syndrome or patients who undergo cancer chemotherapy or organ transplantation, are particularly susceptible to opportunistic fungal infections. Although Candida species continue to be the major pathogenic fungi in these patients, cryptococcosis, aspergillosis, and coccidioidomycosis, among others, have become increasingly important mycoses. Antifungal drugs currently being used in clinic include polyene antibiotics, azole derivatives and 5-fluorocytosine. With the exception of the latter, all other drugs possess mechanisms of action aimed at disrupting the integrity of the fungal cell membrane by either interfering with the biosynthesis of membrane sterols or by inhibiting sterol functions. However, one significant obstacle preventing successful antifungal therapy is the dramatic increase in drug resistance, especially against azole antimycotics. Among the major mechanisms by which fungi invoke drug resistance is the overexpession of extrusion pumps able to facilitate the efflux of cytotoxic drugs from the cell thus leading to decreased drug accumulation and diminished concentrations. Since the initial observations that azole resistance by fungi may be caused by overexpression of multidrug efflux transporter genes, significant advances have been achieved primarily with Saccharomyces cerevisiae and Candida albicans. The purpose of this review is to discuss various aspects of multidrug resistance in fungi such as antifungal drug mechanisms of action and fungal molecular genetics in the context of targeted drug discovery. The role that membrane transporter proteins play in drug resistance in various species of Candida, Aspergillus and Cryptococcus will be address in more detail, as will be their importance as selective drug targets in the design of novel antifungal agents.

Abnormal platelet reactivity has been linked to unstable angina, myocardial infarction, post angioplasty stenosis, cerebral ischemia, thrombotic stroke and a variety of inflammatory vascular disorders associated with transplantation. Drugs that inhibit blood coagulation, promote fibrinolysis or block platelet activation are important therapeutic agents in cardiovascular medicine. However, many of the current antiplatelet modalities are nonspecific, ineffective or associated with severe side effects that limit their usefulness. In this article, we discuss some basic aspects of platelet pathophysiology to illustrate the importance of ADP stimulation and signaling in platelet activation. CD39, the ATP diphosphohydrolase (ATPDase) expressed on quiescent vascular endothelium, modulates platelet purinoreceptor activity by the sequential hydrolysis of extracellular ATP or ADP directly to AMP. This thromboregulatory potential of CD39 has been recently demonstrated by the generation of mutant mice with disruption of the gene, and by a series of experiments where high level ATPDase expression has been attained by adenoviral vectors in the injured vasculature. Systemic administration of soluble derivatives of CD39 or targeted expression of the native protein to sites of vascular injury may have future therapeutic application.

Chronic interstitial lung diseases including pneumoconiosis have pathological characteristics which alter the lung structure and function consequent to the accumulation and activation of inflammatory cells in the lower respiratory tract. These activated cells usually secrete the inflammatory and fibrogenic mediators. Of the diffuse parenchymal lung diseases, the majority have no known etiology and idiopathic pulmonary fibrosis (IPF) is the diagnosis most frequently encountered by clinicians. Pathogenic similarities between pneumoconiosis and IPF provide a strong basis for hypothesizing that environmental agents may cause IPF. Many case-control studies have been published that provide further evidence for a number of associations between occupational and environmental exposures and IPF. Such reports support a strong evidence that IPF may be a heterogenous disorder associated with a number of environmental exposures. As a model of lung fibrosis, experimental pneumoconiosis is giving us a great information because crystalline silica is probably one of the most typical agent producing pulmonary fibrosis and the severity of its health effects and the widespread nature of exposure have been long recognized. Many papers provide evidence that particles have the potential to cause stimulation of phagocytes to release oxidants and such oxidative stress is believed to be a major factor in pulmonary inflammation followed by fibrotic change. Many kinds of cellular mediators are recognized as a implicating factor in this process including cell-to-cell interaction, enzymes, cytokines, arachidonic acid derivatives et al. Treatment of pneumoconiosis is an attractive and interesting topic. But, the mechanism of pathogenesis of pneumoconiosis is not thoroughly understood yet. Also, whether the process of fibrosis formation be retarded or not is questionable with some therapeutic trial. Therefore, a sensitive biomarker which is possible to estimate the pathological pathway in pneumoconiosis is needed. Our laboratory has studied particulate-induced pulmonary reaction for two decades consistently. This review will focus on signal transduction pathway involved in oxidative stress and some inhibitory agents with pleiotropic mechanism in pulmonary fibrosis. I will also introduce some data of animal studies with multidrug regimen as well.