Current Medicinal Chemistry - Volume 10, Issue 4, 2003

The peroxisome proliferator-activated receptor (PPAR) family of nuclear receptors, a set of three receptor sub-types encoded by distinct genes, function as lipid sensors to regulate a broad range of genes in many metabolically active tissues. Synthetic PPAR agonists have exhibited therapeutic benefits in treating diabetes and cardiovascular diseases. The discovery of PPAR-specific ligands has led to significant advancement in our understanding of the structure of these receptor proteins and the molecular mechanism of their ligand-dependent activation. Herein, we present both recent progress in the functional analysis of these orphan receptors and the confirmation of the PPARs as molecular targets for the development of new medicines to treat human metabolic disease.

Clenbuterol and other β-agonists are commonly misused as repartitioning agents in meat production and as doping substances to improve athletic performance. Numerous reports on food poisoning throughout Europe prompted the EU regulatory offices and FDA to implement a ban on the use of β-agonists as growth promoters. Several analytical methods have been developed for detecting illegal administration of these compounds, based mainly on chromatography and immunoassay screening. This article deals with the pharmacological aspect of β-agonists in growth promotion, control of their abuse and methods of analysis.

Nitric oxide (NO) releasing drugs have helped patients suffering from angina pectoris for more than a century. In the 1970s NO-sensitive guanylyl cyclase was identified as the target of NO. Since then, three different isoforms of the enzyme have been identified. All NO-releasing drugs act by binding of NO to the prosthetic heme group common to all three isoforms. They thus act all as isoform-unspecific substances. This review addresses recently developed drugs that activate NO-sensitive guanylyl cyclase independent of NOrelease. They have great potential in the treatment of angina pectoris, hypertension and erectile dysfunction. The molecular target has been validated by the successful clinical use of NO-releasing drugs for more than a century. At the same time the mode of action of these drugs is entirely new. The development of highly isoform-specific derivatives with distinct pharmacological profiles is now an open possibility with great potential.

Sustained reduction of viral replication can be achieved in HIV infected patients after treatment with combinations of drugs (HAART) that inhibit the viral reverse transcriptase, and protease enzymes. However, replication competent virus can still be recovered from latently infected resting memory CD4+ T-cell lymphocytes. Moreover, ”covert“ virus replication has been demonstrated in patients who experienced reductions in plasma viremia to levels below the limit of detection of the most sensitive PCR assays. In most studies, preferential attention has been given to latent resting CD4+ T-lymphocytes as a source of HIV persistence. However, insufficient suppression of HIV replication could also lead to viral re-emergence after HAART interruption. In addition to CD4+ T- lymphocytes, other host cells such as long-lived resident macrophages or recently infected blood monocytes could also contribute to maintain persistent HIV replication after HAART. Establishing the origin of re-emerging HIV in patients under HAART upon treatment interruption is important to design optimal treatment schemes. Therapeutic strategies aimed at reducing the number of latently infected cells involve immune activation with IL-2, or other stimulatory factors, in the presence of antiretroviral drugs. Elimination of replication-competent virus would require intensification of HAART, or the use of antiretroviral drugs achieving an effective concentration at the site of HIV replication. In this review the mechanisms of HIV persistence and the methods that can be used to distinguish latent from covert HIV replication in different cell types will be discussed.

The three-dimensional structures of active derivatives of N-(substitutedphenylcarbonylamino)-4-(1- hydroxymethylphenyl)-1,2,3,6-tetrahydropyri-dines, which have previously been shown to possess antiinflammatory activities, were built using BIOMEDCAche 5.0 software program. In addition, the three dimensional structures of some of the inactive ones were similarly generated. The conformational analysis, molecular and electronic structures were examined by molecular mechanics and quantum mechanics calculations. The primary objective was to clarify the effects of physicochemical properties of substituents on activity, since the exact role of the substitution pattern on the phenyl ring is uncertain. In addition, the experimental log P values did not appear to have any influence on the anti-inflammatory potencies of these compounds, since compounds having differing lipid solubilities are equiactive. We found that strongly electron-donating group, such as the para-substituted methoxy group, detracts from activity. The conformational analysis indicated that the 4-ethyl derivative had the lowest energy conformation. Except for compound 1, which showed the lowest surface volume, compounds 2-9 had nearly similar surface volumes.

Poly(ADP-ribose) polymerase-1 (PARP-1) is the principal member of the PARP enzyme family consisting of PARP-1 and several recently identified novel poly(ADP-ribosyl)ating enzymes. PARP-1 functions as a DNA damage sensor and signalling molecule. Upon binding to DNA breaks, activated PARP cleaves NAD+ into nicotinamide and ADP-ribose and polymerizes the latter onto nuclear acceptor proteins including histones, transcription factors and PARP itself. This Poly(ADP-ribosyl)ation contributes to inflammatory signal transduction processes. In addition, oxidative stress-induced overactivation of PARP consumes NAD+ and consequently ATP, culminating in cell dysfunction or necrosis. Activation of PARP has been implicated in the pathogenesis of stroke, myocardial ischemia, diabetes, diabetes-associated cardiovascular dysfunction, shock, traumatic central nervous system injury, arthritis, colitis, allergic encephalomyelitis and various other forms of inflammation. Therefore, inhibition of PARP by pharmacological agents may prove useful for the therapy of these diseases, as has been shown in preclinical animal models. Moreover, PARP inhibitors may have additional, potential utility as anticancer agents, radiosensitizers and antiviral agents. In the present article we overview the structures and pharmacological actions of various pharmacological classes of compounds which inhibit the catalytic activity of PARP.

Although liver transplantation has become standard procedure for patients with liver failure, a number of issues in the management of these patients remains to be addressed. Alternative approaches have been tested, such as hepatocytes containing liver-support systems and filtration devices. However, the replacement of detoxification has been difficult, as the majority of toxins accumulating in liver failure is albumin-bound.Albumin dialysis (MARS system) is characterized by the specific removal of albumin-bound toxins through an innovative membrane transport. In particular, the albumin acts as a specific molecular adsorbent that is regenerated on line in a recycling system.Nowadays MARS represents the most frequently used liver support system. This treatment has been shown to remove albumin-bound molecules, such as bilirubin, bile acids, aromatic amino acids and copper. The removal of these toxins is clinically accompanied with an improvement of liver, cardiovascular and renal functions and hepatic encephalopathy.In several trials MARS was found to improve the clinical situation in patients with acute exacerbation of chronic liver failure and acute hepatic failure, but also in hepatorenal syndrome and primary graft non functionor chronic rejection after liver transplantation. In summary, a critical analysis of the literature confirms that MARS device can be a safe therapeutic choice to achieve a better clinical outcome, and, sometimes, a survival advantage in patients with liver failure, even if a multi-center randomized trial is the only reliable way to enforce today's results. Further advances in the MARS components will definitively state whether albumin dialysis may represent the future in the field of artificial liver devices.