1,721,323 research outputs found
Multifunctional Drugs: New challenging chimeras in medicinal chemistry and drug discovery
No full textSpiro-heterocyclic benzopyrane derivatives: new activators of mito- KATP channels as potential cardioprotective agents
No full textNovel adenosine 5'-triphosphate-sensitive potassium channel ligands: a patent overview (2005 - 2010)
No full textIntroduction: ATP-sensitive potassium channels are important metabolic regulators that link cellular metabolism to excitability. Their wide distribution in various tissues and organs makes them significant and topical targets in a large number of diseases.
Areas covered: This review summarizes the current understanding of the molecular biology and pharmacology of KATP channels, and the pathological states that result from aberrant expression or function of these proteins. In particular, relevant research, patents and patent applications of the past 5 years are discussed.
Expert opinion: The tissue-specific KATP channel modulation reflects an early discovery stage in drug design. The wide distribution of KATP channels lets us consider them as valid targets for several pathologies, but on other hand the ubiquitous nature is a relevant drawback in developing an effective therapy because of the onset of side effects related to the lack of selectivity. On this basis, further investigations on both the structures and the localization of each receptor subtype should be carried out either exploring the structure-activity relationship of the already existing KATP ligands or developing new selective fluorescent probes. To date, this research area still strives to design new tissue-targeted ligands that could pave the way to the development of innovative and effective drugs for clinical use
Cardiac ATP-sensitive potassium channels, a potential target for an anti-ischaemic pharmacological strategy
No full textBrief periods of ischaemia induce in the myocardium an increased resistance to the injury due to a subsequent, more prolonged ischaemic episode. This phenomenon, known as ischaemic pre-conditioning (IPC), articulated in two distinct phases (an early and a delayed one), is ensured by different biological mechanisms. Although an exhaustive comprehension of these mechanisms has not yet been reached, it is widely accepted that among the various signals involved as triggers and/or end-effectors, an important role is undoubtedly played by the activation of cardiac ATP-sensitive potassium channels (KATP). In the myocardial cells, KATP channels have been identified both in the sarcolemmal membrane (sarc-KATP) and in the mitochondrial inner membrane (mito-KATP). Although many experimental findings suggest that a role of sarc-KATP channel activation in IPC cannot be excluded, in the last few years, many authors have indicated that this phenomenon could be attributed to the exclusive (or at least prevalent) activation of the mito-KATP channels. Conversely, drugs modulating the KATP channels (as activators or blockers), on one hand, have been employed as useful experimental tools for basic studies on IPC. On the other hand, KATP-openers have been viewed as promising possible therapeutic agents for limiting the myocardial injury due to ischaemic episodes. In particular, those molecules exhibiting a good degree of selectivity towards the mito-KATP channels have been indicated as potential anti-ischaemic cardio-protective pharmacological tools, devoid of other biological effects (such as negative inotropic activity, hypotension or hyperglycaemia) linked to the activation of cardiac and non-cardiac sarcKATP channels. In this paper, we wish to report the experimental evidence supporting the role of sarc- and mito-KATP channels in IPC the relative signalling pathways potentially involved in the mechanisms of cardio-protection and, finally, an overview of the most important molecules acting as activators or blockers of KATP channels, with their selectivity profile
Preparation of 4-spiroheterocyclic 2,2-dimethylchromanes as activators of ATP-sensitive potassium (KATP) channels
No full textNO-releasing hybrids of cardiovascular drugs
No full textNitric oxide (NO) is an endogenous compound, which plays a fundamental role in the modulation of the function of the cardiovascular system. where it induces vasorelaxing and antiplatelet responses, mainly through the stimulation of guanylate cyclase and the increase of cGMP. Many drugs of common, time-honoured clinical use (for example, glycerol trinitrate and all the vasodilator nitrites and nitrates) act via the release of exogenous NO, thus mimicking the effects of the endogenous factor. In the last few years, a revision of the "one-compound-one-target" paradigm has led pharmacologists and pharmaceutical chemists to develop new classes of molecules which combine different pharmacodynamic properties. This innovative pharmacological/pharmaceutical strategy has produced hybrid drugs, with a dual mechanism of action: a) the slow release of nitric oxide and b) another fundamental pharmacodynamic profile. These drugs have been obtained by inserting appropriate NO-donor chemical groups (i.e. nitrate esters, nitrosothiols, etc.), linked to a known drug, by means of a variable spacer moiety. These new pharmacodynamic hybrids present the advantage of combining a basic mechanism of action (for example, cyclooxygenase inhibition, beta-antagonism or ACE inhibition) with a slow release of NO, which may be useful either to reduce adverse side effects (for example, the gastrotoxicity of NSAIDs), or to improve the effectiveness of the drug (for example, conferring direct vasorelaxing and antiplatelet effects on an ACE-inhibitor). The aim of this review is to present the chemical features of NO-releasing hybrids of cardiovascular drugs, and to explain the pharmacological improvements obtained by the addition of the NO-donor properties
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