1,721,547 research outputs found
Large-conductance, Ca2+-activated K+ channels: function, pharmacology and drugs
No full textBecause 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 (K(ATP)) 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, G-proteins, 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 BK-activators, with a description of the lead chemical structures, will be also described
An update on hybrid drugs in cardiovascular drug research
No full textBackground: Several different strategies are commonly used in medicinal chemistry to develop new molecules targeted at improving the current pharmacotherapy of cardiovascular diseases and hypertension. Among these, in the past years, we could observe an increasing development of new hybrid compounds in which two or more mechanisms of action are combined together to give a new pharmacological entity targeting, simultaneously, several factors involved in complex cardiovascular diseases. Objective: The aim of this review is to present the rational pharmacological bases and the chemical approaches used for the development of representative hybrid drugs. Conclusions: In this paper, some promising multi-targeted enzyme inhibitors and dual receptor antagonists are reported. Some examples of pharmacodynamic hybrids compounds, in which a suitable nitric oxide releasing functionality has been added to known cardiovascular drugs, are also shown
An alternative method to evaluate the nature of an antagonist and its potency. A theoretical approach
No full textThe Schild analysis is certainly the most reliable method for antagonism studies. The Schild regression allows one to determine the parameter of the Schild-slope, which represents a powerful diagnostic tool when investigating the nature of an antagonist and, consequently, to evaluate its potency. Nevertheless, in functional pharmacology, often practical reasons lead the experimenter to obtain an inhibition curve for the antagonist and calculate its potency by means of equations, which can be considered as a derivation of the Cheng-Prusoff analysis. This approach is considered theoretically invalid, because it does not allow to know the exact nature of the antagonism, and thus the evaluation of the antagonist dissociation constant can be meaningless. In this paper, a new method is proposed, which, by means of an equation closely similar to the Schild one, permits one to obtain a linear regression analysis, giving a slope value absolutely equivalent to the Schild-slope. This method allows us to determine both the nature and the potency of an antagonist, and requires an experimental procedure substantially analogous to the one performed to obtain an inhibition curve
Valore nutraceutico dei flavonoidi presenti nel genere Citrus. Evidenze epidemiologiche, cliniche e pre-cliniche degli effetti protettivi dei Citrus flavanoni sulle funzioni cardiovascolari
No full textI flavonoidi presenti nei frutti del genere Citrus (costituiti per il 95% da fl avanoni) stanno emergendo per il loro notevole valore nutraceutico. Evidenze epidemiologiche, cliniche e pre-cliniche dimostrano che l’assunzione di frutti appartenenti al genere Citrus riduce, in modo signifi cativo, l’incidenza delle patologie cardiovascolari.
In questo articolo si dà una disamina degli studi che prendono in esame le loro proprietà benefiche, tentando di dar spazio anche al chiarimento dei più importanti meccanismi d’azione
Ventricular arrhythmias. A potential risk associated with the use of non-cardiovascular drugs prolonging the QT interval
No full textThe electrocardiogram shows a sequence of cardiac electrical events generated by individual electrical currents generated mainly by sodium (Na+), potassium (K+) and calcium (Ca++) ions transiting via specialized transport pathways, such as ion channels, inserted in the membranes of excitable cardiac cells. Na+ and Ca++, entering the cells, are messengers of activating, inward, depolarizing currents (INa, ICa), generating the QRS wave of the electrocardiogram, whereas K+, leaving the cells, carries outward repolarizing currents (e.g. Ito, IKr, IKs and IK1), generating the T wave of the electrocardiogram, which drives the cell to a rest condition. Therefore, a significantly prolonged repolarization process results in a prolonged QT interval which can initiate ectopic cardiac beats that may evolve into a potentially lethal ventricular tachyarrhythmia, called torsades de pointes. This implies that the measurement of QT interval, appropriately corrected (QTc) for heart rate values by applying available algorithms, is a current tool of diagnostic investigation to reveal abnormalities of the cardiac repolarisation process. Numerous non cardiovascular drugs in general clinical use (psychotropics, prokinetics, antimalarials, antibiotics, antihistamines, etc.) can prolong QT interval, often by a mechanism not necessary for their therapeutic effects, which is a reduction of the potassium current IKr conveyed by the HERG channel. The torsadogenic potential of these drugs can be facilitated by factors (female gender, bradycardia, electrolyte imbalances, cardiac diseases, simultaneous use of multiple drugs prolonging QT interval, etc.) known to have the propensity to reduce the redundant cardiac repolarization reserve, characterizing the healthy myocardium. Presently, drug candidates are routinely subjected to preclinical and clinical examination for cardiac safety, a property required by health authorities for any new medicine before allowing marketing authorization. Finally, before prescribing a medicinal product prolonging QT interval, a physician should carefully evaluate not only the disease he wants to treat but also the availability of equally effective, alternative drugs. The golden rule, to which such a prescription has always to abide, requires that the beneficial effects expected from a therapy should for each treated patient outweigh any possible adverse consequence, particularly when the latter one could be of lethal nature
Arachidonic Acid Derivatives and Neuroinflammation
No full textNeuroinflammation is characterized by dysregulated inflammatory responses localized within the brain and spinal cord. Neuroinflammation plays a pivotal role in the onset of several neurodegenerative disorders and is considered a typical feature of these disorders. Microglia perform primary immune surveillance and macrophage-like activities within the central nervous system. Activated microglia are predominant players in the central nervous system response to damage related to stroke, trauma, and infection. Moreover, microglial activation per se leads to a proinflammatory response and oxidative stress. During the release of cytokines and chemokines, cyclooxygenases and phospholipase A2 are stimulated. Elevated levels of these compounds play a significant role in immune cell recruitment into the brain. Cyclic phospholipase A2 plays a fundamental role in the production of prostaglandins by releasing arachidonic acid. In turn, arachidonic acid is biotransformed through different routes into several mediators that are endowed with pivotal roles in the regulation of inflammatory processes. Some experimental models of neuroinflammation exhibit an increase in cyclic phospholipase A2, leukotrienes, and prostaglandins such as prostaglandin E2, prostaglandin D2, or prostacyclin. However, findings on the role of the prostacyclin receptors have revealed that their signalling suppresses Th2-mediated inflammatory responses. In addition, other in vitro evidence suggests that prostaglandin E2 may inhibit the production of some inflammatory cytokines, attenuating inflammatory events such as mast cell degranulation or inflammatory leukotriene production. Based on these conflicting experimental data, the role of arachidonic acid derivatives in neuroinflammation remains a challenging issue
Preparation of 4-spiroheterocyclic 2,2-dimethylchromanes as activators of ATP-sensitive potassium (KATP) channels
No full textPotassium channel openers: The case of BK channel activators
No full textLarge-conductance calcium-activated potassium channels, also known as BK or Maxi-K channels, occur in many types of cells, where they play an essential role in the regulation of cell excitability and function. BK channel openers constitute a heterogeneous group of organic compounds being able to activate BK channels and having a wide therapeutic potential for the treatment of different neurological, urological and cardiovascular diseases. This review addresses the novel research on BK channels as drug targets as well as it reports recent developments in the chemistry of BK channel openers and in the chemical structural aspects determining their activity
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