Current Medicinal Chemistry - Volume 9, Issue 1, 2002

Neuronal acetylcholine ion channel receptors (nAChRs), that exist in several subtypes resulting from a different organisation of various subunits around the central ion channel, are involved in a variety of functions and disorders of the central nervous system. There is evidence to implicate a deficit of nAChRs in the symptomatology of severe neurologic pathologies, such as Alzheimer's and Parkinson's diseases. Reliable three-dimensional structures of nAChRs are not available yet, and this hampers adopting structure-based approaches in designing new ligands. Also pharmacophore models are not reliable enough to be used in ligand-based approaches to drug design and little structure-activity work has been reported so far. This paper deals with structure-activity relationships of a wide series of nicotinic ligands. It provides results from a study of the quantitative structure activity relationships (QSARs) based on literature data of about 270 nicotinic agonists, belonging to various chemical classes. The QSAR study was carried out by using either a classical Hansch approach or a Comparative Molecular Field Analysis (CoMFA). Within each congeneric series, Hansch-type equations revealed detrimental steric effects as the factors mainly modulating the receptor affinity, whereas CoMFA allowed us to merge progressively models obtained for each class of congeners into a more general one that showed good crossvalidation statistics. The CoMFA coefficient isocontour maps illustrated, at the 3-D level, the most relevant interactions responsible for a high receptor affinity, whereas the robustness of the global three-dimensional QSAR / CoMFA (n = 206, q2 = 0.749, r2 = 0.847, s= 0.600) model was supported by the high value of the prediction statistics (r2pred = 0.961) and confirmed by the satisfactory predictions of the affinity data of an external set of 18 recently published ligands with chemical structures even quite diverse from those included in the training set.

The clinical effectiveness of morphine is limited by several side effects, including the development of tolerance and dependence. Most of these side effects are believed to be mediated by central opioid receptors therefore, hydrophilic opioids, which don't cross the blood-brain barrier, may have advantages over morphine in some clinical applications. We recently synthesized several analogues of DALDA (Tyr-D-Arg-Phe-Lys-NH2), a highly hydrophilic peptide derived from the endogenous opioid peptide dermorphin; all of them, particularly [Dmt¹] DALDA (Dmt - 2',6'-dimethyl tyrosine), had high potency and selectivity at μ receptors, the target of morphine, in activity assays. Here we report the pharmacological characterization of [Dmt¹] DALDA in the whole animal. [Dmt¹]DALDA was 40 times more potent than morphine in inducing antinociception in mice when both drugs were given s.c., and 6-14 times more potent than DAMGO, a selective μ agonist, when both drugs were given it. However, [Dmt¹]DALDA showed poor cross-tolerance to morphine; thus chronic morphine treatment of animals increased the antinociceptive AD50 of systemic [Dmt1]DALDA two fold or less, as compared to an 8-9-fold increase for morphine and a 4-5-fold increase for DAMGO. The antinociceptive activity of [Dmt¹]DALDA (i.t) was blocked by CTAP, a selective μ antagonist, but not by TIPPΨ, a selectiveδ antagonist, nor by nor-BNI, a selective κ antagonist. [Dmt¹]DALDA-induced antinociception was also blocked by naloxone methiodide, an antagonist that does not cross the blood-brain barrier, when agonist and antagonist were given i.t. or i.c.v., but not when they were given s.c. We conclude that [Dmt¹] DALDA is a highly potent analgesic acting at μ receptors. Though it appears to penetrate the blood-brain barrier, it exhibits low cross-tolerance to morphine, suggesting that it may have advantages over the latter in certain clinical applications.

The cellular electrophysiologic effect of GYKI 16638, a new antiarrhythmic compound was studied and compared with that of sotalol and mexiletine in undiseased human right ventricular muscle preparation by applying the conventional microelectrode technique.GYKI 16638 (5 μM), at stimulation cycle length of 1000 ms, lengthened action potential duration (APD90) from 338.9 ± 28.6 ms to 385.4 ± 24 ms (n = 9, p< 0.05). This APD lengthening effect, unlike that of sotalol (30 μM), was rate-independent. GYKI 16638, contrary to sotalol and like mexiletine (10 μM), exerted a use-dependent depression of the maximal rate of depolarization (Vmax) which amounted to 36.4 ± 11.7 percent at cycle length of 400 ms (n = 5, p p< 0.05) and was characterised with an offset kinetical time constant of 298.6 ± 70.2 ms.It was concluded that GYKI 16638 in human ventricular muscle shows combined Class IB and Class III antiarrhythmic properties, resembling the electrophysiological manifestation seen after chronic amiodarone treatment.

(-)-Deprenyl (selegiline), a propargylamine derivative of methylamphetamine, is a potent, irreversible inhibitor of monoamine-oxidase type B (MAO-B). The MAO-B inhibitory effects of various doses (0.1-0.25-0.5 mg / kg) of (-)-deprenyl in rat brain and liver were compared, using either oral or subcutaneous drug administration. The intensity of the first pass metabolism of (-)-deprenyl was also estimated. The effect of pre-treatment with phenobarbitone (80 mg / kg i.p., daily for three days) or proadifen (SKF-525A, 50 mg / kg i.p., single dose) on the MAO-B inhibitory potency of (-)-deprenyl was also studied. The oral and subcutaneous administration of selegiline induced a significantly different degree of MAO-B enzyme inhibition in the rat brain, but not in the liver. The inhibitory potency of (-)-deprenyl on MAO-B activity was markedly influenced by pre-treatment of rats with an inducer (phenobarbitone), or an inhibitor (SKF-525A) of cytochrome P-450 mono-oxygenases in the liver. Our results suggest, that (-)-deprenyl is metabolised mainly in the liver by microsomal cytochrome P-450 dependent mono-oxygenases, and it has an intensive “first-pass” metabolism. The parent compound is responsible for the inhibition of MAO-B enzyme activity.

A large number of oral antidiabetic agents are available today. This article provides a short review of the pharmacology and some clinical aspects of various oral antidiabetic drugs. It focuses mainly on the newest developing drugs (therapy of the near future) and on the most commonly used older groups for the common approach of every- day practice (sulphonylureas). The primary goal of this review is to compare the electrophysiological effects of glibenclamide in isolated normal and streptozotocin induced diabetic rats and alloxan induced rabbits ventricular preparations, while on the other hand to differentiate the hypoglycaemic sulphonylureas (0.1-1000 μmol / kg) according to their cardiovascular activity in healthy and diabetic animals. In vitro (1-100 μmol / l) as well as chronically treated (5 mg / kg for 10 weeks) glibenclamide prolonged the action potential duration in normal but failed to affect it in diabetic ventricular preparations. Our results suggest that the sensitivity to glibenclamide of KATP channels in diabetic ventricular fibers is drastically decreased. The effects of different sulphonylureas (tolbutamide, glibenclamide, gliclazide, glimepiride) on ventricular ectopic beats as well as the duration of ventricular fibrillation induced by 10 min ischemia / 50 min reperfusion in healthy and diabetic rats were compared. Tolbutamide and gliclazide dose-dependently enhanced both parameters both in healthy and diabetic groups. Glibenclamide in healthy rats increased, while in diabetic rats it decreased the arrhythmogenicity. Glimepiride depressed the arrhythmogenicity in both healthy and diabetic animals. Glimepiride proved to dose-dependently enhance the myocardial tissue flow in dog in contrast to glibenclamide. These results confirm that glimepiride has less cardiovascular actions than other sulphonylureas. From the newest oral antidiabetics this review tries to emphasize the most important basic pharmacological properties, mechanism of action, therapeutic use.

Liver metastases cause the majority of deaths from colorectal cancer, and response to chemotherapy and external radiotherapy is poor. An alternative is internal radionuclide therapy using 90Y labeled microspheres. These microspheres are very stable and have a proven efficacy in the field of treatment of primary or metastatic hepatic cancer. Whilst these glass spheres showed encouraging results in patients, their high density is a serious drawback. Currently, other materials with lower densities and other radioisotopes are being investigated in order to optimize this promising new therapy. Three major radiolabeled microsphere materials, viz. glass, resin-based and polymer-based, are now available for therapy or are being tested in animals. In this review the preparation, stability and degradation of these spheres are discussed.

In the human brain several cell types are capable of initiating and amplifying a brain specific inflammatory response involving the synthesis of cytokines, prostaglandins and oxygen free radicals. In Alzheimer's disease (AD), signs of an inflammatory activation of microglia and astroglia are present inside and outside amyloid deposits. Cell culture and animal models suggest an interactive relationship between inflammatory activation, reduced neuronal functioning and deposition of amyloid. The activation of inflammation-associated enzymes such as p38 mitogen-activated protein kinase (p38 MAPK) and cycloxygenase-2 (COX-2) is not restricted to glial cells but also found in neurons and may contribute to intraneuronal damage. Epidemiological studies have shown a reduced risk of AD among users of anti-inflammatory drugs. Therefore, anti-inflammatory drugs have become the focus of several new treatment strategies. Small clinical trials with non-steroidal anti-inflammatory drugs (NSAIDs) such as indomethacin and diclofenac showed a trend for a disease modifying effect, while clinical trials with steroids did not show a beneficial effect. NSAIDs may not only act on COX-2 but also inhibit COX-1 activity or activate peroxisome proliferator-activated receptor gamma (PPARγ. Among promising new strategies to reduce the inflammatory activation in the CNS interfering with intracellular pro-inflammatory pathways has been shown to be effective in various cell culture and animal models. Inhibitors of p38MAPK and PPARγ agonists may be suitable agents to suppress inflammatory activation in AD.

Non steroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used for inflammation therapy. The major drawback in using the NSAIDs is in their tendency to cause gastrointestinal toxicity. Since the roles of arachidonic acid (A.A) metabolites, as leukotrienes (Lts), prostaglandins (PGs) and thromboxanes (TXA2) as mediators of the inflammatory reaction were clarified, much effort has been made to develop inhibitors of the production of these chemical mediators as anti-inflammatory agents. These mediators also play important roles in some inflammatory or allergic diseases, acting either alone or in combination and inhibitors of 5-lipoxygenase (5-LOX) and / or cyclooxygenase isoforms 1,2 (COX-1,2) may be useful for the treatment of asthma, psoriasis and rheumatoid arthritis. Leukotrienes, the products of 5-LOX metabolism have been associated with immediate hypersensitivity reactions, anaphylaxis and asthma.In addition, active oxygen species (AOS) including superoxide anion (O2-), hydrogen peroxide, hydroxyl radical and ferric radical, mediate cell damage in a variety of pathophysiological conditions and are responsible for oxidative injury of enzymes, lipid membranes and DNA in living cells and tissues. Prostaglandins and leukotrienes in the arachidonate pathway linked with lipid peroxidation may amplify the oxidative damage. Nirtric oxide (NO) plays also a role as an efector in inflammation, since PG and NO thought to be important in maintaining mucosal integrity.Dual or selective inhibitors, specific receptor antagonists, AOS scavengers, and NO donors have been under development for therapeutic application. Several classes of inhibitors have been identified and at least 12 major chemical series are known to affect PGs production directly.In this review, we account on our research work concerning NSAIDs combined with a reference of the recent literature.

Recent contributions applying Computational Chemistry to serotonin-3 and nicotinic acetylcholine ionotropic receptors are reviewed. These two receptors constitute a good example for the examination of the computational protocols that have been used to understand how they work. On the one hand, (5-HT3R) receptor mapping techniques have been mostly employed in its study and very few examples of receptor fitting have been appeared. On the other hand, (nAChR) has been studied mainly from the receptor fitting point of view, although many contributions using receptor mapping exist. In the first case, antagonists seems to be more important that agonists, so more works are devo- ted to them. In the second case, agonist development is the main issue. Although far for being complete, in either of the cases we have working pharmacophores as well as 3D models for their binding sites that are ready to be used as a starting guess to design potential drugs. It is noteworthy that the absence of crystallographic structure for these receptors has motivated the interest in their study, constituting an interesting and challenging field. Mutagenesis experiments have allowed the establishment of main amino acids that are essential in the receptor functioning and then, interaction models have been postulated. Although most of the models are speculative in nature, some of them have been proved to be valuable tools for drug design. This scientific field is already open and many areas are still unexplored. Computational tools for treating these issues exist in a wide variety and their rational application would produce the answers to the structure and functioning of these receptors.

A combination of the economic importance of blood as a resource and the advent of the AIDS epidemic has led to a requirement for improved pathogen screening techniques for donated blood. However, due to “window” periods where infective agents cannot be detected, the ability to disinfect of blood and its derivatives - plasma, platelets and red blood cell concentrates - has assumed great importance.Whereas conventional disinfection techniques such as solvent-detergent treatment or ultra-violet irradiation may be employed in plasma or protein concentrates, the collateral damage associated with such treatments disallows their use with cellular fractions. In many ways the pathogen selectivity required here is akin to standard antimicrobial chemotherapy but is complicated by the requirement for activity against the full range of microbes - viruses, bacteria, yeasts and protozoa - rather than simply antibacterial or antiviral etc. The recent problems due to prion agents in the blood supply mean that such agents should also be included in any proposed disinfective regimen.Several new approaches to microbial disinfection have been proposed by academia and the “blood industrials”: targeted chemotherapy, photochemotherapy and photodynamic antimicrobial chemotherapy.