Current Medicinal Chemistry - Volume 9, Issue 14, 2002

Studies on enzyme inhibition remain an important area of pharmaceutical research since these studies have led to the discoveries of drugs useful in a variety of physiological conditions. The enzyme inhibitors can interact with enzymes and block their activity towards natural substrates. Urease inhibitors have recently attracted much attention as potential new anti-ulcer drugs. Ironically, urease was the first enzyme crystallized but its mechanism of action is still largely misunderstood. This chapter therefore reviews comprehensive developments in the field of urease inhibitors. Inhibitors of urease can be broadly classified into two categories: (1) active site directed (substrate-like), (2) mechanism-based directed. We present here the examples of selected inhibitors along with their mechanisms of action to characterize their mode of urease inhibition. The observations that urease due to its high substrate (urea) specificity can only bind to a few inhibitors with a similar binding mode as urea is also discussed. Several non-covalent interactions including hydrogen bonds and hydrophobic contacts stabilize the enzyme-inhibitor complex. Regardless of the class of compound, it is reported that only a few functional groups with electronegative atoms such as oxygen, nitrogen and sulfur act either as bidentate (mostly), tridentate (rarely), or as ligandchelator to form octahedral complexes with two slightly distorted octahedral Ni ions of the enzyme. Bulky groups attached to the pharmacophore were found to decrease the activity of inhibitors, since the lack of a bulky attachment makes it easier for urease inhibitors to enter the substrate-binding pocket as well as avoid unfavorable steric interactions with amino acid residues in its vicinity. This review is intended to provide highlights of the inhibition of urease by hydroxamic acids (HXAs), phosphorodiamidates (PPDs), imidazoles, phosphazene and related compounds. These compounds are compared to previously reported urease inhibitors for the catalytic models proposed for urease activity. The differences in inhibition of urease activities from plants and of bacterial origin by various inhibitors and physiological implications of urease inhibition are discussed.

Endogenous histamine regulates the haematopoiesis. Histidine decarboxylase inhibitor decreases the histamine level, and its intracellular antagonist decreases the histamine effect. The effect of histidine decarboxylase inhibitor (α-fluoromethyl histidine) and the intracellular antagonist of histamine [NN-diethyl-2-4-(phenylmethyl) phenoxyethan-amine-HCl] was investigated on the colonyforming ability of human peripheral progenitor cells. Semi-solid culture medium was used both in the presence and in the absence of 3 U/ml erythropoietin. α-Fluoromethyl histidine was used in the range of 50 through 150 μ Mol/ml, the concentration of NN-diethyl- 2-4-(phenylmethyl) phenoxyethanamine-HCl was between 5 and 25 μ Mol/ml. The number of both the erythroide and the granulocyte macrophage colony was significantly decreased in a concentration dependent manner by the presence of both NN-diethyl-2-4-(phenylmethyl) phenoxyethanamine-HCl (in all concentrations used) and α-fluoromethyl histidine (at higher concentration). The inhibitory effect was decreased by erythropoietin.

The purpose of this paper was to examine the effects of speech therapy and various pharmacological treatment approaches on the voice and speech of persons with Parkinson's disease (PD). Approximately 80% of PD patients have voice and speech problems including reduced vocal intensity, reduced vocal pitch, monopitch and monoloudness, and imprecise articulation. Research prior to 1970s had not demonstrated significant improvements following speech therapy. However, recent research has shown that speech therapy (when persons with PD are optimally medicated) has proven to be the most efficacious therapeutic method for improving voice and speech function. Across research studies, pharmacological methods of treatment in isolation do not appear to significantly improve voice and speech function in PD. In a single subject study, however, the dopamine agonist Mirapex was shown to have beneficial effects on vocal intensity. Possible explanations for the differential responses to treatment are discussed. It is suggested that the goal of future studies should be investigations of the effects of combined treatment approaches.

The continuous raise of molecular diversity requires to find a guidelines for orientation it this. A likely occasion for consideration of new QSAR approach possibilities for this aspect is the flavonoids (F) multitude, the class of organic compounds (C) with very varied chemistry and pharmacology. The list of F affinities includes benzodiazepines, adenosine, estrogen receptors and row of enzymes - phosphodiesterase, proteinthyrosine kinase, aromatase, xanthine oxidase asf. The simple way of clasterization of C is their numerical representation as the vector in linear space. The components of the some vectors are determined by parameters of molecular shape (number of cycles, tertiary atoms asf) and orbital structure indices (numbers of occupied orbitals of different kind). The nonesterificied F are tricyclic C with numbers of tertiary atoms n = 5,...,11 - and more, from generic flavon (flavan), n = 5, to myricetin (n = 11) and other. The all derivatives of F with given n may be associated with vectors of linear space, σ-set, with linear form σ= 2l + m, l - number of nonhydrogenous atoms, m = 0, ±1,... The collection of σ-sets which numbered by given number n = 5,...11,... envelops all natural F and their derivatives which have not additional cycles. In mentioned σ-sets of tricyclic C by the some mode are presented ligands of benzodiazepines, adenosine, estrogens and other receptors and enzymes. Positions of ligands of each class form a triangle "sector of affinity" in 4-5 adjacent σ-sets. These triangle sectors in mentioned collection of σ-sets are disposed in conformity to certain laws. The position of given F relatively to "sectors of affinity" allow to found their affinity (and cross-affinity) to different targets. Calculations with utilization of sophisticated shape parameters and electronic structure indices allow to determine the affinity and / or activity quantitative measure.

Because of the physiological role played by the hyperpolarisation process resulting from a K+ outflow, it is not surprising that compounds able to activate outward K+ channels are considered as promising drugs, with exciting perspectives for the treatment of several cardiovascular, respiratory, neurological and urological diseases. Among the different and numerous K+ channel families, medicinal chemistry has focused its major interest onto two channel types: the ATP-sensitive channels (KATP) and the large conductance subtype (BK), that belongs to the wide family of calcium-activated K+ channels. BK channels are almost ubiquitous and exhibit single channel conductance of 100-300 pS, a property which justifies the potent role of these channels in the control of the membrane potential. BK channels have been investigated as potential therapeutic targets for different neuropathies, because of their profound influence on the neuronal activity. Moreover, BK channels are expected to have applications for the therapy of cardiovascular diseases. A potent feed-back control of the vascular and non-vascular smooth muscle tone is mediated by these channels, whose activation can be promoted by both a rise of the intracellular free calcium concentration as well as a membrane depolarisation. Additionally, BK channel activation can also be induced by other factors, such as cAMP-mediated phosphorylation, Gproteins, GMP and cGMP. The aim of this paper is to give a concise overview of the biological and pharmacological properties and potential therapeutic applications of activators of BK channels present at the vascular level. The "state of the art" in the pharmaceutical development of natural and synthetic BKactivators, with a description of the lead chemical structures, will be also described.

In the last few years, new drugs for the treatment of schizophrenia have been introduced in therapy which have noticeably improved the quality of life of many schizophrenic patients. These new "atypical" drugs have chemical, pharmacological and clinical properties which are different from those of the classical neuroleptics. The most used drugs among the "atypical" antipsychotics are clozapine, olanzapine, quetiapine and risperidone. Despite several differences in their pharmacokinetic and pharmacodinamic profiles, they show some common properties: e.g. they dont cause extrapyramidal side effects, and they are active against the negative as well as positive symptoms of schizophrenia. The need for clinical monitoring of patients undergoing therapy is still evident because the onset of side effects is often related to high plasma concentrations of the drug. The clinical monitoring of patients can significantly improve the knowledge of pharmacological interactions among different CNS drugs, as well as enhance the compliance of the patients, thus leading to higher treatment efficacy. In order to carry out efficient clinical monitoring, reliable analytical methods are needed to determine the analytes even at very low concentrations and in the presence of other drugs. For this purpose, analytical techniques such as gas or liquid chromatography are often used coupled with sensitive and selective means of detection, such as fluorimetric, electrochemical or mass spectrometry detectors. The most recent studies on the determination of atypical antipsychotics will be reviewed in addition to the issue of sample pretreatment which is a critical step when the analysis of biological fluids is concerned.