Synthesis, molecular modeling, and pharmacological testing of bis-quinolinium cyclophanes: potent, non-peptidic blockers of the apamin-sensitive Ca(2+)-activated K(+) channel.

The synthesis and pharmacological testing of two series of novel bis-quinolinium cyclophanes as blockers of the apamin-sensitive Ca(2+)-activated K(+) (SK(Ca)) channel are presented. In these cyclophanes the two 4-aminoquinolinium groups are joined at the ring N atoms (linker L) and at the exocyclic N atoms (linker A). In those cases where A and L contain two or more aromatic rings each, the activity of the compound is not critically dependent upon the nature of the linkers. When A and L each have only one benzene ring, the blocking potency changes dramatically with simple structural variations in the linkers. One of these smaller cyclophanes having A = benzene-1,4-diylbis(methylene) and L = benzene-1, 3-diylbis(methylene) (3j, 6,10-diaza-1,5(1,4)-diquinolina-3(1,3),8(1, 4)-dibenzenacyclodecaphanedium tritrifluoroacetate, UCL 1684) has an IC(50) of 3 nM and is the most potent non-peptidic SK(Ca) channel blocker described to date. Conformational analysis on the smaller cyclophanes using molecular modeling techniques suggests that the differences in the blocking potencies of the compounds may be attributable to their different conformational preferences.

La comunicación científica: ¿arte o técnica? / Scientific Communication: art o technique?

El último fin del científico es comunicar la información de la forma más comprensible y rápida y se necesitan algunas pautas para cumplir este objetivo. Este artículo intenta orientar y responder a cuestiones que pueden surgir a los autores que desean escribir artículos o exponer una comunicación oral, ahorrarles tiempo y asegurarles claridad y coherencia. La exposición oral es una responsabilidad pero, también, es una oportunidad única que puede proporcionar grandes satisfacciones, después de seguir un mínimo de reglas básicas (AU)

Synthesis, molecular modeling, and K+ channel-blocking activity of dequalinium analogues having semirigid linkers.

Dequalinium [1,1'-(decane-1, 10-diyl)bis(2-methyl-4-aminoquinolinium)] is an effective blocker of the small conductance Ca2(+)-activated K+ channel. It has been shown that the number of methylene groups in the alkyl chain linking the two quinolinium rings of this type of molecule is not critical for activity. To further investigate the role of the linker, analogues of dequalinium have been synthesized, in which the alkyl chain has been replaced by CH2XCH2 where X is a rigid or semirigid group containing aromatic rings. The compounds have been tested for blockade of the slow after-hyperpolarization on rat sympathetic neurons. The most potent compounds have X = phenanthryl, fluorenyl, cis-stilbene, and C6H4(CH2)nC6H4, where n = 0-4. The conformational preferences of the compounds were investigated using the XED/COSMIC molecular modeling system. Although there is some dependence of the potency of the analogue on the conformational properties of the linker (X), overall, X groups having substantial structural differences are tolerated. It seems that X provides a support for the two quinolinium groups and does not interact with the channel directly. The intramolecular separation between the quinolinium rings, which is provided by rigid groups X, is not critical for activity; this may be attributed to the residual conformational mobility of the heterocycles and to the extensive delocalization of the positive charge. These two factors may permit favorable contacts between the quinolinium groups and the channel over a range of intramolecular separations.

Discrimination between subtypes of apamin-sensitive Ca(2+)-activated K+ channels by gallamine and a novel bis-quaternary quinolinium cyclophane, UCL 1530.

1. Gallamine, dequalinium and a novel bis-quaternary cyclophane, UCL 1530 (8,19-diaza-3(1,4),5(1,4)-dibenzena-1 (1,4),7(1,4)-diquinolina-cyclononadecanephanedium) were tested for their ability to block actions mediated by the small conductance, apamin-sensitive Ca(2+)-activated K+ (SKCa) channels in rat cultured sympathetic neurones and guinea-pig isolated hepatocytes. 2. SKCa channel block was assessed in sympathetic neurones by the reduction in the slow afterhyperpolarization (AHP) that follows an action potential, and in hepatocytes by the inhibition of the SKCa mediated net loss of K+ that results from the application of angiotensin II. 3. The order of potency for inhibition of the AHP in sympathetic neurones was UCL 1530 > dequalinium > gallamine, with IC50 values of 0.08 +/- 0.02, 0.60 +/- 0.05 and 68.0 +/- 8.4 microM respectively, giving an equi-effective molar ratio between gallamine and UCL 1530 of 850. 4. The same three compounds inhibited angiotensin II-evoked K+ loss from guinea-pig hepatocytes in the order dequalinium > UCL 1530 > gallamine, with an equi-effective molar ratio for gallamine to UCL 1530 of 5.8, 150 fold less than in sympathetic neurones. 5. Dequalinium and UCL 1530 were as effective on guinea-pig as on rat sympathetic neurones. 6. UCL 1530 at 1 microM had no effect on the voltage-activated Ca2+ current in rat sympathetic neurones, but inhibited the hyperpolarization produced by direct elevation of cytosolic Ca2+. 7. Direct activation of SKCa channels by raising cytosolic Ca2+ in hepatocytes evoked an outward current which was reduced by the three blockers, with dequalinium being the most potent. 8. These results provide evidence that the SKCa channels present in guinea-pig hepatocytes and rat cultured sympathetic neurones are different, and that this is not attributable to species variation. UCL 1530 and gallamine should be useful tools for the investigation of subtypes of apamin-sensitive K+ channels.