Search

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., Ministerio de Educación yCiencia, Ministerio de Sanidad y Consumo, Instituto deSalud Carlos III, UniversidadComplutense de Madrid, Fundación LILL, Centro Nacional de Investigaciones Cardiovasculares, Depto. de Farmacología y Toxicología, Fac. de Medicina, TRUE, pub

Objective: This study was undertaken to analyze whether nitric oxide (NO) modulates the human potassium channel hKv1.5, which generates the ultrarapid delayed rectifier current (IKur) that determines the height and duration of atrial action potentials. Methods: Currents were recorded using the whole-cell patch-clamp in Ltk- cells expressing hKv1.5 channels. Results: The NO donors (+/-)-S-Nitroso-N-acetylpenicillamine (SNAP) and sodium nitroprusside, a NO solution, and l-Arginine inhibited hKv1.5 currents in a concentration-dependent manner. The NO concentration in the cell chamber was monitored using a sensor, and the IC50 for NO-induced hKv1.5 block was 340+/-70 nM. SNAP also inhibited the IKur recorded in mouse ventricular myocytes. The NO effects were partially mediated by the activation of the soluble guanylate cyclase (sGC)/cGMP/cGMP-dependent protein kinase (PKG) pathway. The biotin-switch assay demonstrated the presence of S-nitrosylated cysteines (Cys) on the hKv1.5 protein in SNAP-treated cells. Molecular modeling of hKv1.5 channel structure suggests that S-nitrosylation of Cys331 (segment 2, S2) and Cys346 (S2) would be stabilized by hydrogen bridge bonds with Ile262 (S1) and Arg342 (S2), respectively. Conclusions: NO inhibits the hKv1.5 current by a cGMP-dependent mechanism and by the S-nitrosylation of the hKv1.5 protein, an effect that contributes to shaping the human atrial action potentials., Mutua Madrileña Foundation, Red HERACLES, Depto. de Farmacología y Toxicología, Fac. de Medicina, TRUE, pub

Two oximes derived from 3-methyl-3-azabicyclo[3.2.1]octan-8-one (I) and 3-methyl-3-azabicyclo[3.3.1]nonan-9-one (II) were synthesized and studied by IR, 1H and 13C NMR spectroscopy. Compound I adopts in CDCl3 a chair-envelope conformation with the N–CH3 group in equatorial position. Compound II adopts a flattened chair–chair conformation with N–CH3 substituent in equatorial disposition.

A series of amides derived from syn and anti 2-methyl-2-azabicyclo[2.2.2]octan-5-amines has been synthesized and studied by IR, Raman, 1H and 13C NMR spectroscopy. The crystal structure of 2-methyl-5-syn-(4-quinolinecarboxamide)-2-azabicyclo[2.2.2]octane Id has been determined by X-ray diffraction. It has been found that syn amides present a preferred conformation in CDCl3 solution, with the CH3-N bond in exo position. This is also observed for compound Id in the solid state. However, for anti amides the CH3-N bond adopts a favoured endo position. A conformational analysis using molecular modelling techniques was undertaken in order to gain additional information.

The structural study of several esters derived from syn and anti 5-arylcarbonyloxy-2-methyl-2-azabicyclo[2.2.2]octane hydrochlorides, has been carried out by infrared and Raman spectroscopy. In the case of 2-methyl-5anti-(3-pyridincarbonyloxy)-2-azabicyclo[2.2.2]octane dihydrochloride, the crystal structure has been determined by X-ray diffraction. The spectral differences found between syn and anti epimers and between mono and dihydrochlorides are discussed.

A series of 3,7-dimethyl-9-[(N-substituted)-4-chlorobenzamido]-3,7-diazabicyclo[3.3.1]nonane-9-carboxamides1–3 have been synthesized and studied by infrared, Raman, H and C NMR spectroscopy and molecular modeling techniques. The crystal structure of 3,7-dimethyl-9-[(N-benzyl)-4-chlorobenzamido]-3,7-diazabicyclo[3.3.1]nonane-9-carboxamide (2) was determined by X-ray diffraction. In CDCl and CDOD solutions, these compounds adopt a non-distorted chair-chair conformation with the N-substituents in an equatorial position. Compound 2 prevented acetic acid induced writhing in mice. © 1995, All rights reserved.

A series of amides derived from 3,7-dimethyl-3,7-diazabicyclo[3.3.1]nonan-9-amine (I) have been synthesized and examined by IR, 1H and 13C NMR spectroscopy, and the crystal structure of 9-(3-indolycarboxamido)-3,7-dimethyl-3,7-diazabicyclo[3.3.1]nonane hydrochloride (IV·HCl) has been determined by X-ray diffraction. The 1H and 13CNMR data of the parent amine (I) are also included. These compounds adopt an almost perfect chair-chair conformation with the NCH3 groups in the equatorial position.

The methyl 2,6-diphenyl-1-methyl-4-oxopiperidine-3,5-dicarboxylates 1 were synthesized by the Mannich procedure from methyl 3-oxoglutarate, benzaldehyde and methylamine. Keto-enol tautomerism as well as configurational isomerism at C-2 were observed. The stereochemistry of the Ib and Ic enolic forms were determined by H and C nmr data. Copyright © 2013 HeteroCorporation.

The vibrational (IR and Raman) and H and C NMR spectra of the analgesic and anti‐inflammatory benzidamine salicylate (Benzasal) have been examined, and the results are described. The crystal structure of this compound has been determined by X‐ray diffraction. To assist in interpretation of the spectroscopic data, some measurements of benzidamine, benzidamine hydrochloride, and salicylic acid have also been made. The most important intermolecular interactions of benzidamine salicylate in the solid state are NH…C hydrogen bonds involving both salicylate oxygen atoms (d = 2.658 Å and 3.228 Å). At least the stronger hydrogen bond remains in CDCl solution. Moreover, the strong intramolecular hydrogen bond O‐H……C within the salicylate anion has also been observed in the solid state and in solution.

The synthesis and preliminary analytical assessment of di(2-pyridyl)-N,N-di[(8-quinolyl)-amino]methane is reported. It shows some potential as a reagent for iron(II).

The IR spectra of 3-alkyl-3-azabicyclo(3.2.1)octane-8-spiro-, 3-alkyl-3-azabicyclo(3.3.1) nonane-9-spiro-, and 8-alkyl-8-azabicyclo(4.3.1)decane-10-spiro-5'-hydantoins have been studied in the solid state and in solution and the existence of different types of hydrogen bonding deduced from the spectra. The presence of intermolecular N-H⋯N bonds in the solid state depends mainly on the steric hindrance of the polymethylene chain and on the bulk and shape of the piperidine -substituent. The possibility of strong N-H⋯N bond formation is smaller than for isomeric nortropane- and granatanine-spirohydantoins. Results are confirmed in some cases by Raman and X-ray measurements.

Tropane-3-spiro-4'-imidazol-5'-one has been synthesized and its crystal and molecular structures determined by X-ray diffraction, IR, Raman, 1H-NMR and 13C-NMR methods. The tautomeric equilibrium between this structure and the corresponding conjugated form in different solvents is also studied from IR and UV data. The imidazoline ring, the spiranic C(3, 4'), the N(8) and the methyl C(9) atoms are situated in a plane. The piperidine ring adopts a distorted chair conformation in the crystalline form and in solution. The flattening of the C(1), C(2), C(3, 4'), C(4), C(5) part of the chair and the opposite puckering are noticeably large. In order to complete the results, some spectroscopic measurements have also been made for the tropane-3-spiro-4'-imidazol-5'-one hydrochloride. © 1981.

The 1H and 13C NMR, IR and Raman spectra of several cis and trans propenylphosphonic acid derivatives have been measured and discussed. In some compounds NMR chemical shifts and IR data suggest that the PO and CC groups are in a planar s-trans disposition. © 1986.

3-Methyl-7-alkyl-3,7-diazabicyclo [3.3.1] nonan-9-ones and 9-ols have been studied by 1H, 13C NMF_IR and Raman spectroscopy and the crystal structure of 3,7-dimethyl-3,7-diazabicyclo[8.3.1] nonan-9-ol has been determined by X-ray diffraction. The ketones studied adopt in CDCl3 and (CD3)2SO solution a flattened chair-chair conformation; however, in the crystalline N-methyl N-benzyl derivative, the bicyclic system adopts a chair-boat conformation. X-ray data for 3,7-dimethyl-3,7-diazabicyclo [3.3.1] nonan-9-ol have revealed that the compound has crystallized in a chair-chair conformation stabilized by water and ethanol molecules. Frc.a IR data the existence of another chair anhydrous crystalline form stabilized by intramolecular hydrogen bonding has been deduced. The preferred conformation in solution of the diazabycyclanols mainly depends on the polarity of the solvent. © 1985.

The IR and Raman spectra of 3-methyl-7-alkyl-3,7-diazabicyclo(3.3.1)nonane-9-spiro-5′-hydantoi ns have been studied in the solid state and in deuterium oxide solution. The crystalline spirohydantoins are of three types: (1) those containing strong N3′H⋯N bonds and N1H⋯O=C2 bonds between pairs of molecules; (2) those of predominantly zwitterionic structure in the solid state and (3)_those of predominantly hydrated zwitterionic structure in the solid state. All the compounds exists as zwitterions in aqueous solution. © 1983.