Vasopressin receptor antagonists: pharmacological tools and potential therapeutic agents

The present survey deals with the development and applications of non-peptidergic vasopressin receptor antagonists. The existence of at least three vasopressin receptors (V(1), V(2) and V(3) respectively) is firmly established. V(1)-receptors play a relevant role in the regulation of vascular tone, whereas V(2)-receptors are known to mediate the antidiuretic activity of vasopressin at the level of the renal collecting ducts. The V(3)-receptor appears to be involved in the release of the adreno-corticotropic hormone. Vasopressin receptor antagonists which are peptides have been known for several decades, more recently, both V(1)- and V(2)-receptor blockers which are non-peptidergic have been introduced, as well as agents with affinity for both V(1)- and V(2)-receptor subtypes. A survey of these non-peptidergic antagonists is presented here. Such compounds are useful as pharmacological tools, and they can also be thought of as therapeutic agents as therapeutic agents in cardiovascular and renal diseases. Selective V(1)- and V(2)-receptor antagonists were used to study the interaction between vasopressin receptors and sympathetic neurones. Depending on the experimental model used this interaction can occur at either the pre- or postsynaptic sites. In both cases predominantly V(1)-receptors are involved. A brief survey is given of the potential use of V-receptor antagonists in the drug therapy of syndrome of inappropriate antidiuretic hormone secretion and other water retaining disorders, congestive heart failure and certain forms of hypertension (in particular in the Negroid hypertensive patients).     

Thiophenes and furans derivatives: a new class of potential pharmacological agents

A new class of potential pharmacological thiophenes and furans compounds has been prepared. The obtained thiophenes and furans derivatives were screened for anti-inflammatory, antinociceptive and antioxidant activity in rats. In vitro hepatic ALA-D activity was also evaluated. Thiophene 2 exhibited higher anti-inflammatory effect than thiophenes 1 and 3. However, compound 1 demonstrated lower IC(50) for lipid peroxidation than 2 and 3 in liver and brain. Furan compounds 4-6 presented similar anti-inflammatory activity. The acetylenic furans 4 and 5 inhibited scarcely lipid peroxidation at low concentration as 10 μM. Conversely, furan compound 6 was the most effective against lipid peroxidation in liver. Furans 4 and 5 inhibited lipid peroxidation, in brain, only in high concentrations. In contrast, furan 6 protected (90%) against lipid peroxidation at 10 μM. Thiophene 1 was devoid of anti-inflammatory activity but was efficient in reducing acetic acid-induced constriction. Conversely, it analogue furan 4 presented anti-inflammatory and antinociceptive activity. Thiophene and furan inhibited hepatic ALA-D only at high concentrations. All compounds displayed antioxidant activity however the anti-inflammatory activity is not related to antioxidant potential.     

mTOR-blocking agents in advanced renal cancer: an emerging therapeutic option

Background: The mammalian target of rapamycin (mTOR) pathway inhibition has emerged as one of the main directions for the development of new targeted agents in renal cell carcinoma (RCC). A prominent member in its class of medications, temsirolimus has already been shown to improve overall survival in advanced kidney cancer, when compared with the previous standard, IFN-α. Objective: The aim of this study was to review the most relevant preclinical and clinical data on the mTOR inhibitors, both in clinical use or in current development. Methods: The authors give a comprehensive review of the existing English literature on the role of the mTOR pathway in renal tumorigenesis, as well as a detailed safety and efficacy analysis of older and newer rapamycin analogs. Results/conclusions: Rapamycin derivatives temsirolimus and everolimus have significant clinical activity in patients with advanced-stage RCC. Both parenteral and oral formulations of mTOR inhibitors have shown clinical efficacy and are currently being developed. Combinations of mTOR inhibitors with VEGF/VEGFR-blocking agents are also being studied, in an attempt to further enhance the antineoplastic effect.     

Tick histamine-binding proteins and related lipocalins: potential as therapeutic agents

Tick histamine-binding proteins bind histamine with high affinity and specificity. This is attained by a novel binding mechanism, whereby histamine is sequestered within a binding cavity of the lipocalin fold. The histamine binding proteins and related protein family members are currently under investigation as potential therapeutic agents for the treatment of various diseases, including conjunctivitis, allergic rhinitis, carcinoid syndrome and rheumatoid arthritis. While these proteins show great therapeutic potential, they are part of a diverse family of tick lipocalin proteins, some of which have been implicated in tick-host rejection and host pathogenesis. As such, the therapeutic mining of tick lipocalins should be considered within the framework of the rest of the family.     

Artemisinin-derived dimers as potential anticancer agents: Current developments,action mechanisms,and structure–activity relationships

Anticancer agents play a pivotal role in cancer treatment. However, most of the anticancer drugs currently used in the clinics have a severe anticancer scenario, as well as low specificity and fatal side effects. Thus, there is an urgent demand to develop novel drugs with great efficacy, high specificity, and low side effects. Artemisinin and its semisynthetic derivatives are mainstays of chemotherapy against malaria, and artemisinin-based compounds, especially artemisinin-derived dimers, also exhibit excellent in vitro and in vivo anticancer activity. The structure–activity relationship (SAR) demonstrated that the linker between the two artemisinin moieties influenced the anticancer activity significantly; so, the rational design of the linker may provide valuable therapeutic intervention for the treatment of cancer. This review outlines the potential anticancer activity of artemisinin-derived dimers tethered by different linkers. The SARs, as well as mechanisms of action, are discussed to provide insights for the rational design of more effective dimers.     

Antiproliferative and apoptotic activity of new indazole derivatives as potential anticancer agents

To develop potent and selective anticancer agents, a series of novel polysubstituted indazoles was synthesized and evaluated for their in vitro antiproliferative and apoptotic activities against two selected human cancer cell lines (A2780 and A549). Several compounds showed an interesting antiproliferative activity, with IC₅₀ values ranging from 0.64 to 17 µM against both cell lines. The most active indazoles were then tested in different pharmacological dilution conditions, adding five new cell lines (A2780, A549, IMR32, MDA-MB-231, and T47D) as targets, confirming their antiproliferative activity. Furthermore, selected compounds were able to trigger apoptosis to a significant extent and to cause, in part, a block of cells in the S phase of the cell cycle, with a concomitant decrease of cells in the G2/M and/or G0/G1 phases and the generation of hypodiploid peaks. However, molecule 7d caused a great increase of cells in G2/M and the appearance of polyploid cells. Altogether, our results suggest a good pharmacological activity for our selected polysubstituted indazoles, which are suggestive of a preferential mechanism of action as cell cycle-specific antimetabolites or as an inhibitor of enzyme activities involved in DNA synthesis, except for 7d , which, on the contrary, seems to have a mechanism involving the microtubule system.     

Novel and emerging drugs for systemic lupus erythematosus: mechanism of action and therapeutic activity

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by B cell hyperactivity and defective T-cell function, and several cytokine aberrations, with high titer production of autoantibodies and clinical involvement in multiple organ systems. It can present with a wide variety of symptoms, most commonly involving the skin, joints, kidneys, and blood vessels. Patients with mild SLE can be treated with non-steroidal antiinflammatory drugs and antimalarials. Corticosteroids, azathioprine and cyclophosphamide, remain important for long term management of most patients with active disease. In recent years, significant progress in molecular and cellular biology of SLE has resulted in a better characterization and understanding of the biology and prognosis of this disease. These achievements have provided new opportunities for the development of innovative, more effective, therapies. Novel agents potentially useful in the treatment of patients with SLE include tolerogens, monoclonal antibodies and other agents. Tolerogens are synthetic molecules that can bind and cross-link autoantibodies on reactive B-cell surface, promoting B-cell depletion or inactivity. An anti-DNA antibody based peptide, pCons, might have also therapeutic efficacy in SLE patients who are positive for anti-DNA antibodies. In addition, prasterone, a proprietary synthetic dehydroepiandrosterone product is under investigation for the treatment of SLE. Blockade of TLR9 with specific G-rich DNAoligonucleotids also suppresses lupus activity. Several newer mAbs have been developed and are being evaluated in phase I/II clinical trials. These include newer anti-CD20 mAbs, anti-cytokine therapies, anti-BLys mAbs and anti-C5 mAbs. Most of the new agents which could be potentially useful in the treatment of patients with SLE need further laboratory investigations and clinical trials. In this review, promising new agents, potentially useful in SLE, are presented.     

Antiarrhythmic drugs in atrial fibrillation: an overview of new agents,their mechanisms of action and potential clinical utility

Despite recent advances in our understanding of the mechanism of atrial fibrillation (AF), effective treatment remains difficult in many patients. Pharmacotherapy remains the mainstay of treatment and includes control of ventricular rate as well as restoration and maintenance of sinus rhythm. The currently available antiarrhythmic drugs are particularly effective in converting paroxysmal AF to sinus rhythm and in enhancing the positive effect of electrical cardioversion, but are limited in their efficacy in maintaining sinus rhythm. Moreover, there are limited options in the setting of co-existing ischaemic heart disease, left ventricular dysfunction and structural heart diseases. New drugs added to our clinical armamentarium have been, or are being, developed to combine better efficacy and lack of pro-arrhythmic effects. These developments have gained more interest particularly with the recent debate over rate control versus rhythm control for AF. Although some of these agents are promising, their uptake in clinical practice will not only depend on their efficacy as antiarrhythmic agents but also on their safety in acutely terminating AF and in long-term maintenance of sinus rhythm or rate control in the community.     

Antiarrhythmic drugs in atrial fibrillation: an overview of new agents, their mechanisms of action and potential clinical utility

Despite recent advances in our understanding of the mechanism of atrial fibrillation (AF), effective treatment remains difficult in many patients. Pharmacotherapy remains the mainstay of treatment and includes control of ventricular rate as well as restoration and maintenance of sinus rhythm. The currently available antiarrhythmic drugs are particularly effective in converting paroxysmal AF to sinus rhythm and in enhancing the positive effect of electrical cardioversion, but are limited in their efficacy in maintaining sinus rhythm. Moreover, there are limited options in the setting of co-existing ischaemic heart disease, left ventricular dysfunction and structural heart diseases. New drugs added to our clinical armamentarium have been, or are being, developed to combine better efficacy and lack of pro-arrhythmic effects. These developments have gained more interest particularly with the recent debate over rate control versus rhythm control for AF. Although some of these agents are promising, their uptake in clinical practice will not only depend on their efficacy as antiarrhythmic agents but also on their safety in acutely terminating AF and in long-term maintenance of sinus rhythm or rate control in the community.     

Review article: potential therapeutic applications and mechanisms of action of heparin in inflammatory bowel disease

Unfractioned heparin was recently reported to be beneficial in the treatment of inflammatory bowel disease. The available uncontrolled data show that it may be effective in steroid-resistant ulcerative colitis with a percentage of complete clinical remission of over 70% after an average of 4-6 weeks of therapy. The administration of unfractioned heparin is not currently justified by the very limited available data. The worsening of rectal bleeding is infrequent in treated ulcerative colitis patients and only rarely does it require blood transfusion or a colectomy. Low molecular weight heparin was used in a single trial in patients with steroid-refractory ulcerative colitis, with results similar to those observed with unfractioned heparin. Since a prothrombotic state has been described in inflammatory bowel disease, and microvascular intestinal occlusion seems to play a role in the pathogenesis of inflammatory bowel disease, it is reasonable that part of the beneficial effects of unfractioned heparin in inflammatory bowel disease may result from its anticoagulant properties. However, beyond its well-known anticoagulant activity, unfractioned heparin also exhibits a broad spectrum of immunomodulating and anti-inflammatory properties, by inhibiting the recruitment of neutrophils and reducing pro-inflammatory cytokines. Moreover, it can restore the high-affinity receptor binding of basic fibroblast growth factor and this would aid healing of the ulcerated mucosa. In conclusion, unfractioned heparin may represent a safe therapeutic option for severe, steroid-resistant ulcerative colitis, although randomized, controlled trials are needed to confirm these data.     

Nucleoside natural products and related analogs with potential therapeutic properties as antibacterial and antiviral agents

Nucleoside natural products possess a variety of interesting biological activities, including antibacterial, antiviral and antitumor properties, and are therefore expected to be potential candidates for developing drugs. Complex nucleoside natural products exhibiting antibacterial activity by specific inhibition of bacterial cell wall peptidoglycan biosynthesis are described. In addition to the class of antibacterial nucleoside natural products, the newest members of nucleoside natural products exhibiting interesting antiviral activity are briefly described. In spite of promising properties, no nucleoside natural products and their analogs are presently used in the clinic. A global structure–activity relationship of these classes of nucleoside natural products clearly indicates that it is very important to: i) modulate the cell entry ability; and ii) simplify hydrophilic core structures in order to reduce the size of molecules and stabilize the chemically labile structure.     

Antitumor efficacy and apoptotic activity of substituted chloroalkyl 1H-benz[de]isoquinoline-1,3-diones: a new class of potential antineoplastic agents

A series of ten chloroalkyl 1H-benz[de]isoquinoline-1,3-diones (naphthalimides) were synthesized and evaluated for antitumor activity. Amongst them, new compounds 2d and 2i carrying a 6-NO₂ substituent in the aromatic portion of the molecule possessed significant antineoplastic activity. The most active compound 2i had elicited significant cytotoxicity in 15 human tumor cell lines namely Leukemia: MOLT-4, HL-60; Lymphoma: U-937; Colon: 502713, HT-29, SW-620, HCT-15, COLO-205; Liver: Hep-2; Prostate DU-145, PC-3; Breast: MCF-7; Neuroblastoma: IMR-32, SK-N-SH and Ovary: OVCAR-5 out of the 17 cell lines screened. Flow cytometric analysis performed to study the effect of compound 2i on the progression of cell cycle of MOLT-4 cells, revealed rise in sub-G₁ fraction and concomitant accumulation of cells in S and G₂/M phases, indicating apoptosis, mitotic arrest and/or delay in exit of daughter cells from mitotic cycle respectively. It also induced caspase-mediated apoptosis of MOLT-4 cells in a dose dependant manner. Light and electron microscopic studies revealed characteristic morphology of apoptotic MOLT-4 cells after in vitro treatment with 10 μM concentration of the compound. Apoptosis induction was also observed in HL-60 cells by compounds 2d and 2i to an extent much greater than camptothecin and cis-platin at 10 μM concentration. Both the compounds have shown minimal suppressive effect on human PBMC having high IC₅₀ values of 3,582 and 1,536 μM respectively. These compounds inhibited DNA and RNA synthesis in murine ascites Sarcoma-180 tumor cells in vitro at 8 μM concentration. Above results indicate promising chemotherapeutic potential of the key compound 2i.     

Antipsychotic drugs: evolving mechanisms of action with improved therapeutic benefits

One of the conundrums of neuropharmacology is to understand the therapeutic mechanisms of action of antipsychotic drugs. Every drug with antipsychotic activity is a dopamine (DA) D(2)-like receptor antagonist and therefore this function is critical to reducing psychotic symptoms. However, the actions of the archetypal atypical antipsychotic drug clozapine go beyond antipsychotic effects because the drug is efficacious in treating psychotic symptoms that do not respond to drugs mainly directed at antagonizing the DA D(2) receptor, has benefits in cognition and has recently been shown to reduce levels of suicide. A growing understanding of the mechanisms of clozapine and other atypical antipsychotic drugs suggests that both partial and inverse agonism, as well as receptor antagonism, at specific neurotransmitter receptors is required to give full therapeutic benefits. It is, therefore, timely to review the evolving nature of the mechanisms of action of different antipsychotic drugs.     

The Urocortins: mechanisms of cardioprotection and therapeutic potential

The study of the Urocortin family of peptides is becoming increasingly important clinically, as new discoveries have revealed that their roles in the body are extremely diverse. They range from being involved in the aetiology of affective disorders, boosting the immune system, to cardioprotection during ischaemia and reperfusion injury. Therefore, it is important to understand how these peptides become activated, how they activate different cell types and finally their intracellular signalling pathways. Such studies may enable scientists to develop clinical therapies based on their mechanism of action, which may be used to alleviate a diverse range of pathologies.     

Chitosan oligosaccharide as potential therapy of inflammatory bowel disease: therapeutic efficacy and possible mechanisms of action

Inflammatory bowel disease (IBD) results from intestinal epithelial barrier defect and dysregulated mucosal immune response. This study aimed to evaluate the therapeutic potential of chitosan oligosaccharide (COS), a biodegradation product of dietary fiber chitosan, in the treatment of IBD and to elucidate its possible mechanisms of action. Oral administration of COS protected against mortality and intestinal inflammation in a mouse model of acute colitis induced by 5% dextran sulfate sodium (DSS). The most effective dose range of COS was 10-20 mg/kg/day. In addition, nuclear factor kappa B (NF-κB) activation, and levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in colonic tissues were suppressed in mice receiving COS. Similar protective effect of COS against mortality and intestinal inflammation was observed in another mouse model of acute colitis induced by rectal instillation of 4% acetic acid. Importantly, COS administration after colitis induction was effective in ameliorating intestinal inflammation in both acute colitis models induced by 5% DSS and chronic colitis models induced by cycles of 2.5% DSS. In human colonic epithelial cells (T84 cells), COS treatment prevented NF-κB activation, production of TNF-α and IL-6, and loss of epithelial barrier integrity under both lipopolysaccharide (LPS) and TNF-α-stimulated conditions. Furthermore, binding of LPS to T84 cells, and TNF-α and oxidative stress-induced apoptosis of T84 cells were prevented by treatment with COS. These results suggest that COS may be effective in the treatment of IBD through inhibition of NF-κB signaling and apoptosis of intestinal epithelial cells.