Optical Control of GABAA Receptors with a Fulgimide-Based Potentiator

Optogenetic and photopharmacological tools to manipulate neuronal inhibition have limited efficacy and reversibility. We report the design, synthesis, and biological evaluation of Fulgazepam, a fulgimide derivative of benzodiazepine that behaves as a pure potentiator of ionotropic γ-aminobutyric acid receptors (GABA_ARs) and displays full and reversible photoswitching in vitro and in vivo. The compound enables high-resolution studies of GABAergic neurotransmission, and phototherapies based on localized, acute, and reversible neuroinhibition.     

Simultaneous determination of the magnitude and the sign of multiple heteronuclear coupling constants in 19 F or 31P‐containing compounds

The presence of a highly abundant passive nucleus (Z = ¹⁹ F or ³¹P) allows the simultaneous determination of the magnitude and the sign of up to three different heteronuclear coupling constants from each individual cross‐peak observed in a 2D ¹H‐X selHSQMBC spectrum. Whereas J(HZ) and J(XZ) coupling constants are measured from E.COSY multiplet patterns, J(XH) is independently extracted from the complementary IPAP pattern generated along the detected F2 dimension. The incorporation of an extended TOCSY transfer allows the extraction of a complete set of all these heteronuclear coupling constants and their signs for an entire ¹H subspin system. ¹H‐X/¹H‐Y time‐shared versions are also proposed for the simultaneous measurement of five different couplings (J(XH), J(YH), J(XZ), J(YZ), and J(ZH)) for multiple signals in a single NMR experiment. Copyright © 2015 John Wiley & Sons, Ltd.     

Structure, bioactivity and synthesis of natural products with hexahydropyrrolo[2,3-b]indole

Research on natural products containing hexahydropyrrolo[2,3-b]indole (HPI) has dramatically increased during the past few years. Newly discovered natural products with complex structures and important biological activities have recently been isolated and synthesized. This review summarizes the structures, biological activities, and synthetic routes for natural compounds containing HPI, emphasizing the different strategies for assembling this motif. It covers a broad range of molecules, from small alkaloids to complex peptides.     

Accurate measurement of JHH in overlapped signals by a TOCSY‐edited SERF Experiment

Selective refocusing (GSERF or the recent PSYCHEDELIC) experiments were originally designed to determine all proton–proton coupling constants (J_HH) for a selected proton resonance. They work for isolated signals on which selective excitation can be successfully applied but, as it happens in other selective experiments, fail for overlapped signals. To circumvent this limitation, a doubly‐selective TOCSY‐GSERF scheme is presented for the measurement of J_HH in protons resonating in crowded regions. This new experiment takes advantage of the editing features of an initial TOCSY transfer to uncover hidden resonances that become accessible to perform the subsequent frequency‐selective refocusing. Copyright © 2016 John Wiley & Sons, Ltd.     

Residual dipolar couplings in short peptides reveal systematic conformational preferences of individual amino acids

Residual dipolar couplings (RDCs) observed by NMR in solution under weak alignment conditions can monitor average net orientations and order parameters of individual bonds. By their simple geometrical dependence, RDCs bear particular promise for the quantitative characterization of conformations in partially folded or unfolded proteins. We have systematically investigated the influence of amino acid substitutions X on the conformation of unfolded model peptides EGAAXAASS as monitored by their (1)H(Nu)-(15)N and (1)H(alpha)-(13)C(alpha) RDCs detected at natural abundance of (15)N and (13)C in strained polyacrylamide gels. In total, 14 single amino acid substitutions were investigated. The RDCs show a specific dependence on the substitution X that correlates to steric or hydrophobic interactions with adjacent amino acids. In particular, the RDCs for the glycine and proline substitutions indicate less or more order, respectively, than the other amino acids. The RDCs for aromatic substitutions tryptophane and tyrosine give evidence of a kink in the peptide backbone. This effect is also observable for orientation by Pf1 phages and corroborated by variations in (13)C(alpha) secondary shifts and (3)J(HNH)(alpha) scalar couplings in isotropic samples. RDCs for a substitution with the beta-turn sequence KNGE differ from single amino acid substitutions. Terminal effects and next neighbor effects could be demonstrated by further specific substitutions. The results were compared to statistical models of unfolded peptide conformations derived from PDB coil subsets, which reproduce overall trends for (1)H(Nu)-(15)N RDCs for most substitutions, but deviate more strongly for (1)H(alpha)-(13)C(alpha) RDCs. The outlined approach opens the possibility to obtain a systematic experimental characterization of the influence of individual amino acid/amino acid interactions on orientational preferences in polypeptides.     

1,3-Dipolar cycloadditions of electrophilically activated benzonitrile N-oxides. Polar cycloaddition versus oxime formation

The reactions of electrophilically activated benzonitrile N-oxides (BNOs) toward 3-methylenephthalimidines (MPIs) have been studied using density functional theory (DFT) at the B3LYP/6-31G* level. For these reactions, two different channels allowing the formation of the [3 + 2] cycloadducts and two isomeric (E)- and (Z)-oximes have been characterized. The 1,3-dipolar cycloadditions take place along concerted but highly asynchronous transition states, while formation of the oximes is achieved through a stepwise mechanism involving zwitterionic intermediates. Both reactions are initiated by the nucleophilic attack of the methylene carbon of the MPIs to the carbon atom of the electrophilically activated BNOs. The analysis based on the natural bond orbital (NBO) and the topological analysis of the electron localization function (ELF) at the transition structures and intermediates explains correctly the polar nature of these reactions. Solvent effects considered by the PCM model allow explaining the low incidence of the solvent polarity on the rate and composition of the reactions.     

Embedding theorems and integration operators on Bergman spaces with rapidly decreasing weights

We completely describe those positive Borel measures μ in the unit disc D such that the Bergman space Ap(w)⊂Lq(μ), 0<p,q<∞, where w belongs to a large class W of rapidly decreasing weights which includes the exponential weights , α>0, and some double exponential type weights.As an application of that result, we characterize the boundedness and the compactness of Tg:Ap(w)→Aq(w), 0<p,q<∞, w∈W, where Tg is the integration operator

     

Invariant pre-foliations for non-resonant non-uniformly hyperbolic systems

Given an orbit whose linearization has invariant subspaces satisfying some non-resonance conditions in the exponential rates of growth, we prove existence of invariant manifolds tangent to these subspaces. The exponential rates of growth can be understood either in the sense of Lyapunov exponents or in the sense of exponential dichotomies. These manifolds can correspond to ``slow manifolds', which characterize the asymptotic convergence.

Let be a regular orbit of a dynamical system . Let be a subset of its Lyapunov exponents. Assume that all the Lyapunov exponents in are negative and that the sums of Lyapunov exponents in do not agree with any Lyapunov exponent in the complement of Denote by the linear spaces spanned by the spaces associated to the Lyapunov exponents in We show that there are smooth manifolds such that and . We establish the same results for orbits satisfying dichotomies and whose rates of growth satisfy similar non-resonance conditions. These systems of invariant manifolds are not, in general, a foliation.