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Both increase and decrease of cardiac inward rectifier current (I K1 ) are associated with severe cardiac arrhythmias. Flecainide, a widely used antiarrhythmic drug, exhibits ventricular proarrhythmic effects while effectively controlling ventricular arrhythmias associated with mutations in the gene encoding Kir2.1 channels that decrease I K1 (Andersen syndrome). Here we characterize the electrophysiological and molecular basis of the flecainide-induced increase of the current generated by Kir2.1 channels (I Kir2.1 ) and I K1 recorded in ventricular myocytes. Flecainide increases outward I Kir2.1 generated by homotetrameric Kir2.1 channels by decreasing their affinity for intracellular polyamines, which reduces the inward rectification of the current. Flecainide interacts with the HI loop of the cytoplasmic domain of the channel, Cys311 being critical for the effect. This explains why flecainide does not increase I Kir2.2 and I Kir2.3 , because Kir2.2 and Kir2.3 channels do not exhibit a Cys residue at the equivalent position. We further show that incubation with flecainide increases expression of functional Kir2.1 channels in the membrane, an effect also determined by Cys311. Indeed, flecainide pharmacologically rescues R67W, but not R218W, channel mutations found in Andersen syndrome patients. Moreover, our findings provide noteworthy clues about the structural determinants of the C terminus cytoplasmic domain of Kir2.1 channels involved in the control of gating and rectification.T he cardiac inwardly rectifying K + current (I K1 ) stabilizes resting membrane potential (RMP) close to the reversal potential of K + (E K ) and shapes the final repolarization phase of the action potential (AP) (1). Three inwardly rectifying channels (Kir2.1, Kir2.2, and Kir2.3) contribute to I K1 in the human heart assembled as homo-and/or heterotetramers (2). Experimental data suggest that in humans, Kir2.1 is the major isoform underlying ventricular I K1 , whereas its relative contribution to atrial I K1 seems to be lower (3). The strong inward rectification of Kir2.x channels, i.e., the preferential conduction of inward compared with outward current, depends on the binding of intracellular Mg 2+ and polyamines to the cytoplasmic pore and to the inner vestibule of the channel (4).Gain-and loss-of-function mutations in the gene that encodes Kir2.1 (KCNJ2) have been reported, and both the I K1 increase and decrease produced by these mutations are associated with severe ventricular arrhythmias (1). Furthermore, experimental data showed that as the amplitude of the outward component of the I K1 increases, the frequency of the fast and stable reentry of spiral waves (rotors) increases. Indeed, the importance of I K1 in the establishment of rotors and ventricular fibrillation dynamics has been shown (5).Flecainide is a class I antiarrhythmic drug that, besides its Na + channel-blocking properties, exhibits class III antiarrhythmic effects [i.e., prolongs AP duration (APD) and refractoriness] at the atrial but not at the ventricular le...

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The therapy of complex neurodegenerative diseases requires the development of multitarget-directed drugs (MTDs). Novel indole derivatives with inhibitory activity towards acetyl/butyrylcholinesterases and monoamine oxidases A/B as well as the histamine H receptor (H3R) were obtained by optimization of the neuroprotectant ASS234 by incorporating generally accepted H3R pharmacophore motifs. These small-molecule hits demonstrated balanced activities at the targets, mostly in the nanomolar concentration range. Additional in vitro studies showed antioxidative neuroprotective effects as well as the ability to penetrate the blood-brain barrier. With this promising in vitro profile, contilisant (at 1 mg kg i.p.) also significantly improved lipopolysaccharide-induced cognitive deficits.

1,8-Naphthyridine derivatives related to 17 (ITH4012), a neuroprotective compound reported by our research group, have been synthesized. In general, they have shown better inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) than most tacrine derivatives previously synthesized in our laboratory. The compounds presented an interesting neuroprotective profile in SH-SY5Y neuroblastoma cells stressed with rotenone/oligomycin A. Moreover, compound 14 (ethyl 5-amino-2-methyl-6,7,8,9-tetrahydrobenzo[b][1,8]naphthyridine-3-carboxylate) also caused protection in cells stressed with okadaic acid (OA) or amyloid beta 1-42 peptide (Abeta(1-42)). Interestingly, compound 14 prevented the OA-induced PP2A inhibition, one of the enzymes implicated in tau dephosphorylation. This compound also exhibited neuroprotection against neurotoxicity elicited by oxygen and glucose deprivation in hippocampal slices. Because these stressors caused neuronal damage related to physiopathological hallmarks found in the brain of Alzheimer's disease (AD) patients, we conclude that compound 14 deserves further in vivo studies in AD models to test its therapeutic potential in this disease.