Light-Dark Adaptation of Channelrhodopsin Involves Photoconversion between the all-trans and 13-cis Retinal Isomers.

Channelrhodopsins (ChR) are light-gated ion channels of green algae that are widely used to probe the function of neuronal cells with light. Most ChRs show a substantial reduction in photocurrents during illumination, a process named "light adaptation". The main objective of this spectroscopic study was to elucidate the molecular processes associated with light-dark adaptation. Here we show by liquid and solid-state nuclear magnetic resonance spectroscopy that the retinal chromophore of fully dark-adapted ChR is exclusively in an all-trans configuration. Resonance Raman (RR) spectroscopy, however, revealed that already low light intensities establish a photostationary equilibrium between all-trans,15-anti and 13-cis,15-syn configurations at a ratio of 3:1. The underlying photoreactions involve simultaneous isomerization of the C(13)═C(14) and C(15)═N bonds. Both isomers of this DAapp state may run through photoinduced reaction cycles initiated by photoisomerization of only the C(13)═C(14) bond. RR spectroscopic experiments further demonstrated that photoinduced conversion of the apparent dark-adapted (DAapp) state to the photocycle intermediates P500 and P390 is distinctly more efficient for the all-trans isomer than for the 13-cis isomer, possibly because of different chromophore-water interactions. Our data demonstrating two complementary photocycles of the DAapp isomers are fully consistent with the existence of two conducting states that vary in quantitative relation during light-dark adaptation, as suggested previously by electrical measurements.

Asymmetric hydrogenation of α,ß-unsaturated carboxylic esters with chiral iridium N,P ligand complexes.

Enantioselective conjugate reduction of a wide range of α,ß-unsaturated carboxylic esters was achieved using chiral Ir N,P complexes as hydrogenation catalysts. Depending on the substitution pattern of the substrate, different ligands perform best. α,ß-Unsaturated carboxylic esters substituted at the α position are less problematic substrates than originally anticipated and in some cases α-substituted substrates actually reacted with higher enantioselectivity than their ß-substituted analogues. The resulting saturated esters with a stereogenic center in the α or ß position were obtained in high enantiomeric purity.

Crystal structure of (E)-1,2-bis-(4-bromo-2,6-di-fluoro-phen-yl)diazene.

In the crystal, mol-ecules of the centrosymmetric title compound, C12H4Br2F4N2, are linked into strands along [011] by weak C-H⋯F contacts. Furthermore, the mol-ecules are π-π stacked with perpendicular ring distances of 3.4530 (9) Å.

AzoCholine Enables Optical Control of Alpha 7 Nicotinic Acetylcholine Receptors in Neural Networks.

Nicotinic acetylcholine receptors (nAChRs) are essential for cellular communication in higher organisms. Even though a vast pharmacological toolset to study cholinergic systems has been developed, control of endogenous neuronal nAChRs with high spatiotemporal precision has been lacking. To address this issue, we have generated photoswitchable nAChR agonists and re-evaluated the known photochromic ligand, BisQ. Using electrophysiology, we found that one of our new compounds, AzoCholine, is an excellent photoswitchable agonist for neuronal α7 nAChRs, whereas BisQ was confirmed to be an agonist for the muscle-type nAChR. AzoCholine could be used to modulate cholinergic activity in a brain slice and in dorsal root ganglion neurons. In addition, we demonstrate light-dependent perturbation of behavior in the nematode, Caenorhabditis elegans.

Asymmetric hydrogenation of alkenes lacking coordinating groups.

Asymmetric hydrogenation of olefins is one of the most important reactions for the synthesis of optically active compounds, especially in industry. Chiral iridium catalysts based on P,N ligands have strongly expanded their application range. In contrast to rhodium and ruthenium diphosphine complexes they do not require the presence of a coordinating group near the C=C bond and, therefore, allow highly enantioselective hydrogenations of largely unfunctionalized alkenes.

Arylaminoethyl carbamates as a novel series of potent and selective cathepsin S inhibitors.

We report a novel series of noncovalent inhibitors of cathepsin S. The synthesis of the peptidomimetic scaffold is described and structure-activity relationships of P3, P1, and P1' subunits are discussed. Lead optimization to a non-peptidic scaffold has resulted in a new class of potent, highly selective, and orally bioavailable cathepsin S inhibitors.

Synthesis and SAR of arylaminoethyl amides as noncovalent inhibitors of cathepsin S: P3 cyclic ethers.

The synthesis and structure-activity relationship of a series of arylaminoethyl amide cathepsin S inhibitors are reported. Optimization of P3 and P2 groups to improve overall physicochemical properties resulted in significant improvements in oral bioavailability over early lead compounds. An X-ray structure of compound 37 bound to the active site of cathepsin S is also reported.

Synthesis and evaluation of arylaminoethyl amides as noncovalent inhibitors of cathepsin S. Part 3: heterocyclic P3.

A series of N(alpha)-2-benzoxazolyl-alpha-amino acid-(arylaminoethyl)amides were identified as potent, selective, and noncovalent inhibitors of cathepsin S. Structure-activity relationships including strategies for modulating the selectivities among cathepsins S, K, and L, and in vivo pharmacokinetics are discussed. A X-ray structure of compound 3 bound to the active site of cathepsin S is also reported.