ALBERT

Notizen: Summary Structurally guided design approaches to low-molecular-weight platelet aggregation antagonists addressing the platelet-associated heterodimeric cell surface receptor gpIIb/IIIa rely on comparative studies of an ensemble of conformationally and biologically characterized compounds, since no high-resolution structure of the receptor system is available. We report a classical indirect and comparative pharmacophore refinement approach based on a series of small cyclic Arg-Gly-Asp (RGD) peptides as gpIIb/IIIa-fibrinogen interaction antagonists. These peptides have previously been investigated as potent and selective tumor cell adhesion inhibitors. The definition of geometrical descriptors classifying the RGD peptide conformations and their subsequent analysis over selected RGD- and RXD-containing protein structures allows for a correlation of distinct structural features for platelet aggregation inhibition. An almost parallel alignment of the Arg and Asp side chains was identified by a vector analysis as being present in all active cyclic hexa-and pentapeptides. This orientation is induced mainly by the constraint of backbone cyclization and is not of any covalent tripeptide-inherent origin, which was rationalized by a 500 ps high-energy MD simulation of a sequentially related linear model peptide. The incorporation of the recognition tripeptide Arg-Gly-Asp into the cyclic peptide templates acted as a filter mechanism, restricting the otherwise free torsional relation of both side chains to a parallel orientation. Based on the derived results, several detailed features of the receptor binding site could be deduced in terms of receptor complementarity. These findings should govern the design of next-generation compounds with enhanced activities. Furthermore, the complementary stereochemical characteristics of the substrate can be used as boundary conditions for pseudoreceptor modelling studies that are capable of reconstructing a hypothetical binding pocket, qualitatively resembling the steric and electronic demands of gpIIb/IIIa. It is interesting to note that these features provide clear differentiation to requirements for inhibition of % MathType!MTEF!2!1!+-% feaafiart1ev1aaatCvAUfeBSjuyZL2yd9gzLbvyNv2CaerbuLwBLn% hiov2DGi1BTfMBaeXatLxBI9gBaerbd9wDYLwzYbItLDharqqtubsr% 4rNCHbGeaGqiVu0Je9sqqrpepC0xbbL8F4rqqrFfpeea0xe9Lq-Jc9% vqaqpepm0xbba9pwe9Q8fs0-yqaqpepae9qq-f0-yqaqVeLsFr0-vr% 0-vr0db8meaabaqaciGacaGaaeqabaWaaeaaeaaakeaacaqGXoWaaS% baaSqaaiaabAfadaWgaaadbaaabeaaaSqabaGccaqGYoWaaSbaaSqa% aiaaiodaaeqaaaaa!3DDC!\[{\text{\alpha }}_{{\text{V}}_{} } {\text{\beta }}_3 \] substrate binding. This can account for the extremely high selectivity and activity of some of our constrained peptides for either the % MathType!MTEF!2!1!+-% feaafiart1ev1aaatCvAUfeBSjuyZL2yd9gzLbvyNv2CaerbuLwBLn% hiov2DGi1BTfMBaeXatLxBI9gBaerbd9wDYLwzYbItLDharqqtubsr% 4rNCHbGeaGqiVu0Je9sqqrpepC0xbbL8F4rqqrFfpeea0xe9Lq-Jc9% vqaqpepm0xbba9pwe9Q8fs0-yqaqpepae9qq-f0-yqaqVeLsFr0-vr% 0-vr0db8meaabaqaciGacaGaaeqabaWaaeaaeaaakeaacaqGXoWaaS% baaSqaaiaab+bbcaqGIbaabeaakiaabk7adaWgaaWcbaGaaG4maaqa% baaaaa!3E56!\[{\text{\alpha }}_{{\text{b}}} {\text{\beta }}_3 \] or the % MathType!MTEF!2!1!+-% feaafiart1ev1aaatCvAUfeBSjuyZL2yd9gzLbvyNv2CaerbuLwBLn% hiov2DGi1BTfMBaeXatLxBI9gBaerbd9wDYLwzYbItLDharqqtubsr% 4rNCHbGeaGqiVu0Je9sqqrpepC0xbbL8F4rqqrFfpeea0xe9Lq-Jc9% vqaqpepm0xbba9pwe9Q8fs0-yqaqpepae9qq-f0-yqaqVeLsFr0-vr% 0-vr0db8meaabaqaciGacaGaaeqabaWaaeaaeaaakeaacaqGXoWaaS% baaSqaaiaabAfaaeqaaOGaaeOSdmaaBaaaleaacaaIZaaabeaaaaa!3DA4!\[{\text{\alpha }}_{\text{V}} {\text{\beta }}_3 \] receptor.

Notizen: Abstract Time-dependent spin autocorrelation functions and their spectral densities for the semi-infinite one-dimensionals=1/2 XY and XXZ models atT=∞ are determined in part by rigorous calculations in the fermion representation and in part by the recursion method in the spin representation. Boundary effects yield valuable new insight into the different dynamical processes which govern the transport of spin fluctuations in the two models. The results obtained for theXXX model bear the unmistakable signature of spin diffusion in the form of a squareroot infrared divergence in the spectral density.

Notizen: Abstract We present a direct link between manifestations of classical Hamiltonian chaos and quantum nonintegrability effects as they occur in quantum invariants. In integrable classical Hamiltonian systems, analytic invariants (integrals of the motion) can be constructed numerically by means of time averages of dynamical variables over phase-space trajectories, whereas in near-integrable models such time averages yield nonanalytic invariants with qualitatively different properties. Translated into quantum mechanics, the invariants obtained from time averages of dynamical variables in energy eigenstates provide a topographical map of the plane of quantized actions (quantum numbers) with properties which again depend sensitively on whether or not the classical integrability condition is satisfied. The most conspicuous indicator of quantum chaos is the disappearance of quantum numbers, a phenomenon directly related to the breakdown of invariant tori in the classical phase flow. All results are for a system consisting of two exchange-coupled spins with biaxial exchange and single-site anisotropy, a system with a nontrivial integrability condition.

Notizen: Abstract Cardiac arrhythmias can be treated by endocardial laser photocoagulation of arrhythmogenic foci. Transcatheter continuous wave Nd-YAG laser (1064 nm) photocoagulation was studied for impairment of atrioventricular (AV) conduction. First, studies on the dose-effect relation revealed that in vitro applications to ventricular endocardium produce dose-dependent coagulation necrosis. However, energy absorption varies in tissue specimens from different experimental animals and humans and may be dependent on differences in surfaces ultrastructure. Ten times more energy is required for human endocardial specimens than for canine endocardium. The long-term in vivo experiment demonstrates that the chronic laser-induced myocardial lesion size is proportional to the applied energy, exhibit no arrhythmogenic effects and may thus be suitable for the treatment of cardiac arrhythmias. Transcatheter laser application using a combined electrode-laser catheter reliably achieved a slowing of atrioventricular AV conduction (AV modification) or a complete AV block. Thus, the transcatheter application of Nd-YAG laser energy at the AV node may be useful for treatment of tachyarrhythmias in man.