Precision determination of band offsets in strained InGaAs/GaAs quantum wells by C-V-profiling and Schroedinger-Poisson self-consistent simulation

The results of measurements and numerical simulation of charge carrier distribution and energy states in strained quantum wells In_xGa_{1-x}As/GaAs (0.06 < x < 0.29) by C-V-profiling are presented. Precise values of conduction band offsets for these pseudomorphic QWs have been obtained by means of self-consistent solution of Schroedinger and Poisson equations and following fitting to experimental data. For the conduction band offsets in strained In_xGa_{1-x}As/GaAs - QWs the expression DE_C(x) = 0.814x - 0.21x^2 has been obtained.Comment: 9 pages, 12 figures, RevTeX

Semisynthetic analogues of toxiferine I and their pharmacological properties at α7 nAChRs, muscle-type nAChRs, and the allosteric binding site of muscarinic M2 receptors

[Image: see text] A new series of analogues of the calabash curare alkaloid toxiferine I was prepared and pharmacologically evaluated at α7 and muscle-type nAChRs and the allosteric site of muscarinic M(2) receptors. The new ligands differ from toxiferine I by the absence of one (2a–c) or two (3a–c) hydroxy groups, saturation of the exocyclic double bonds, and various N-substituents (methyl, allyl, 4-nitrobenzyl). At the muscle-type nAChRs, most ligands showed similar binding to the muscle relaxant alcuronium, indicating neuromuscular blocking activity, with the nonhydroxylated analogues 3b (K(i) = 75 nM) and 3c (K(i) = 82 nM) displaying the highest affinity. At α7 nAChRs, all ligands showed a moderate to low antagonistic effect, suggesting that the alcoholic functions are not necessary for antagonistic action. Compound 3c exerted the highest preference for the muscle-type nAChRs (K(i) = 82 nM) over α7 (IC(50) = 21 μM). As for the allosteric site of M(2) receptors, binding was found to be dependent on N-substitution rather than on the nature of the side chains. The most potent ligands were the N-allyl analogues 2b and 3b (EC(0.5,diss) = 12 and 36 nM) and the N-nitrobenzyl derivatives 2c and 3c (EC(0.5,diss) = 32 and 49 nM). The present findings should help delineate the structural requirements for activity at different types of AChRs and for the design of novel selective ligands

Rational design of dualsteric GPCR ligands: quests and promise

Dualsteric ligands represent a novel mode of targeting G protein-coupled receptors (GPCRs). These compounds attach simultaneously to both, the orthosteric transmitter binding site and an additional allosteric binding area of a receptor protein. This approach allows the exploitation of favourable characteristics of the orthosteric and the allosteric site by a single ligand molecule. The orthosteric interaction provides high affinity binding and activation of receptors. The allosteric interaction yields receptor subtype-selectivity and, in addition, may modulate both, efficacy and intracellular signalling pathway activation. Insight into the spatial arrangement of the orthosteric and the allosteric site is far advanced in the muscarinic acetylcholine receptor, and the design of dualsteric muscarinic agonists has now been accomplished. Using the muscarinic receptor as a paradigm, this review summarizes the way from suggestive evidence for an orthosteric/allosteric overlap binding to the rational design and experimental validation of dualsteric ligands. As allosteric interactions are increasingly described for GPCRs and as insight into the spatial geometry of ligand/GPCRcomplexes is growing impressively, the rational design of dualsteric drugs is a promising new approach to achieve fine-tuned GPCR-modulation. British Journal of Pharmacology (2010) 159, 997–100