Ryszard Czarnecki

Effects of a Carane Derivative Local Anesthetic on a Phospholipid Bilayer Studied by Molecular Dynamics Simulation

Molecular dynamics (MD) simulations of two hydrated palmitoyloleoylphosphatidylcholine (POPC) bilayers each containing eight carane derivative (KP-23) local anesthetic (LA) molecules in neutral (POPC-LA) or protonated (POPC-LAH) forms were carried out to investigate the effect of KP-23 and its protonation on the bilayer. 3-ns trajectories were used for analyses. A pure POPC bilayer was employed as a reference system. In both POPC-LA and POPC-LAH systems a few KP-23 molecules intercalated into the bilayer and moved near the bilayer/water interface. They were located on the hydrophobic core side of the interface in the POPC-LA bilayer, but on the water phase side in the POPC-LAH bilayer. The order of the POPC chains was higher in the POPC-LA bilayer than in the pure POPC bilayer and was lower in the POPC-LAH bilayer. Interactions between polar groups of KP-23 and POPC or water were responsible for a lower hydration of POPC headgroups in POPC bilayers containing KP-23 than in the pure POPC bilayer. KP-23 molecules were found to form aggregates both in POPC-LA and POPC-LAH bilayers. Due to higher amphiphilicity of LAH, the LAH aggregate was more micelle-like and larger than the LA one. The results demonstrate the rapid timescales of the initial processes that take place at and near the bilayer interface as well as details of the atomic level interactions between local anesthetic and the lipid matrix of a cell membrane.

Stereochemistry of terpene derivatives. Part 3: Hydrolytic kinetic resolution as a convenient approach to chiral aminohydroxyiminocaranes with local anaesthetic activity

Abstract We have developed a stereoselective hydrolytic kinetic resolution process for diastereoisomeric mixtures of epoxyiminocarene intermediates in the presence of ( R , R )-(−)-(salen)Co(III)OAc catalyst, this was applied as the first step in the synthesis of novel chiral aminohydroxyiminocarane derivatives with local anaesthetic activity. The absolute configuration of the product was confirmed by X-ray crystallography.

The effect of (—)-4-(2-hydroxy-3(N-isopropylamino)-propoxyimino)-cis-carane on basal and forskolin-stimulated accumulation of cyclic AMP in the cerebral cortical slices of the rat

Abstract— (–)‐4‐(2‐Hydroxy‐3(N‐isopropylamino)‐propoxyimino)‐cis‐carane, a local anaesthetic and platelet aggregation inhibitor which is much more potent than lignocaine, facilitated forskolin‐induced cyclic (c) AMP accumulation in cerebral cortical slices of the rat. Lignocaine was ineffective in this respect. It is hypothesized that a cAMP‐related mechanism may be involved in increased efficacy of the compound.