Stereoselectivity in central analgesic action of tocainide and its analogs

The antiarrhythmic drug tocainide (5a) and some related chiral α-amino and α-imino anilides (5b–e) were synthesized in optically active form. The antinociceptive effects of the different stereoisomers of these compounds were examined and it was found that the analgesic effect of tocainide is due only to its (?)-(R)-enantiomer. Benzyl replacement for methyl group at the stereogenic centre of tocainide causes loss of activity while both enantiomers of the αiminoxilidide 5e and of the strictly related tocainide analog 5d produce an analgesic effect without any stereoselectivity. Pharmacological tests and [³H] quinuclidinyl benzilate ([³H]QNB) binding assay, taken together, seem to show that the antinociceptive effect of (?)-(R)-tocainide, like the analgesia induced by lidocaine, procaine, and mexiletine, is due to a central presynaptic cholinergic mechanism of action. © 1993 Wiley-Liss, Inc.     

Postendocytic vitellin processing in ovarian follicles of the stick insect Carausius morosus (Br.)

Newly laid eggs of the stick insect Carausius morosus contain two native vitellins (Vit A and Vit B). Under denaturing conditions, these vitellins resolved into 3 (A₁, A₂, and A₃) and 2 (B₁ and B₂) polypeptides. All of these polypeptides had counterparts in the female hemolymph from which they were shown to be derived by in vivo labelling. During ovarian development, the 2 vitellins changed both in charge and polypeptide composition. In EV and LV follicles, Vit A resolved into 4 distinct vitellin polypeptides (A₀, A₁, A₂ and A₃). Using a panel of monoclonal antibodies, polypeptide A₀ proved to be immunologically related to polypeptide A₂. In follicles about to begin choriongenesis, polypeptide A₃ was gradually replaced by a lower M_r polypeptide. Over the same time period, polypeptide B₁ changed in charge, but not in M_r. To confirm the existence of a polypeptide processing in C. morosus, ovarian follicles of different developmental stages were exposed in vivo to [³⁵S]-methionine from 6 to 72 h. Data showed that A₀ and B₁ were the polypeptides most heavily labelled after short time exposures to the radioisotope. Polypeptides B₂ and A₃ were also labelled to some extent. With progressively longer exposures, polypeptides A₁ and A₂ also became labelled. In vivo exposure to [³H]-GlcNAc caused all vitellin polypeptides to become heavily labelled. Autoradiographic analysis of ovarian follicles labelled this way showed that, during development, radioactivity was gradually transferred from newly formed yolk spheres in the cortical ooplasm to the central ooplasm. Data were interpreted as suggesting a causal relationship between polypeptide processing and progressive yolk sphere fusion to yield the central ooplasm. © 1993 Wiley-Liss, Inc.     

Noncoded residues as building blocks in the design of specific secondary structures: Symmetrically disubstituted glycines and β-alanine

Structural changes can be induced in a peptide by selective substitution of coded α-amino acid residues by noncoded α-amino acid residues and the consequent production of analogues with modified structure and conformational preferences. In this review article we summarize the solid state structural results and the conformational preferences of two classes of “building blocks”: (a) the linear and cyclic symmetrically α, α-disubstituted glycines in which either two identical n-alkyl groups replace the hydrogen atoms of the glycine residue or a cyclic aliphatic side-chain system is formed by linking the two α-carbon side chains, respectively; and (b) the β-alanine residue. Examples, whenever possible, of the use of these residues for the elucidation of the bioactive conformation in the appropriate biological systems will be given. © 1993 John Wiley & Sons, Inc.     

Hemoprotein models based on a covalent helix-heme-helix sandwich. 3. Coordination properties, reactivity and catalytic application of Fe(III)- and Fe(II)-mimochrome I

 The coordination state of Fe(III)- and Fe(II)-mimochrome I, a covalent peptide-deuteroheme sandwich involving two nonapeptides bearing a histidine residue in a central position, was studied by UV-visible, EPR, and resonance Raman spectroscopy. The ferric and ferrous states of this new iron species mainly exist, at pH 7, in a low-spin hexacoordinate form with two axial histidine ligands coming from the peptide chains. A minor amount of high-spin form for the ferric state is also present at pH 7. However, it is mainly high-spin at pH 2 or in DMSO. Fe(II)-mimochrome I binds CO with an affinity comparable to that of myoglobin and hemoglobin. Fe(III)-mimochrome I reacts with alkylhydroxylamine and arylhydrazines, leading to the corresponding Fe(II)-nitrosoalkyl and Fe(III)-σ-aryl complexes, respectively. These reactions were greatly dependent on the solvent used and on the pH, and were much slower than the corresponding reactions performed by deuterohemin in the presence of excess imidazole. All these results indicate that the reactivity of iron-mimochrome I is controlled by the binding of the peptide chains to the iron. The reactivity shown by this complex at neutral pH is intermediate between that observed for iron porphyrins in the presence of excess imidazole and that of hemoproteins characterized by a strong bis-histidine axial coordination, such as cytochrome b ₅. Fe(III)-mimochrome I is able to catalyze styrene epoxidation by using a [Fe(III)-mimochrome I]/[H₂O₂]/[stryrene] ratio of 1 : 10 : 2000 in phosphate buffer solution (pH 7.2) containing 2% CTAB both under strictly anaerobic conditions and in the presence of oxygen, at 0  °C. Received: 26 May 1998 / Accepted: 20 August 1998     

Effects of Thyroxine on Methionine Adenosyltransferase Activity in Rat Cerebral Cortex and Cerebellum During Postnatal Development

Abstract: Methionine adenosyltransferase (MAT) activity was evaluated in cerebral cortex and cerebellum in controls and in rats treated with thyroxine. In controls the enzyme showed a different pattern in cerebral cortex and cerebellum during neonatal and late suckling periods. Hyperthyroid rats showed a significant increase of the enzyme in cerebral cortex only at the 2nd day of the neonatal period; in cerebellum the developmental pattern of MAT in neonatal period was anticipated temporally by 2–4 days. During the late suckling period thyroxine treatment produced in cerebellum a significant decrease in MAT activity at the 15th day after birth. From these data, we propose that hyperthyroidism may cause precocious induction of MAT both in cerebral cortex and in cerebellum and that the increased availability of S -adenosyll-methionine during the neonatal period could be related to its utilization also in polyamine biosynthesis.     

Peptaibol antibiotics: Conformational preferences of synthetic emerimicin fragments

The ir absorption and CD conformational analyses of solutions of the protected 2–9 fragment of the peptaibol antibiotics emerimicins III and IV \documentclass{article}\pagestyle{empty}\begin{document}$ \rlap{--} (Aib_3 \rlap{--} )L - Val - Gly - L - Leu\rlap{--} (Aib_2 \rlap{--} ) $\end{document} and related short sequences are consistent with the presence of a right-handed α-helix for the octapeptide, while the tri-, tetra-, and pentapeptides adopt a 3₁₀-helix, either right- or left-handed, depending on the amino acid sequences. The structural preferences of solid-state \documentclass{article}\pagestyle{empty}\begin{document}$ Z\rlap{--} (Aib_3 \rlap{--} )L - Val - OMe $\end{document} and \documentclass{article}\pagestyle{empty}\begin{document}$ Z\rlap{--} (Aib_3 \rlap{--} )L - Val - Gly - OMe $\end{document} have been determined by x-ray diffraction. In accord with the solution data, incipient 3₁₀-helices, formed by two and three β-turns, have been found for the tetra- and pentapeptides, respectively. The tetrapeptide helix has the left-handed screw sense, while that of the pentapetide is right-handed, thus confirming the conclusions of the CD analysis of the solution.     

Preferred conformations of peptides containing α,α-disubstituted α-amino acids

The conformational preferences of linear peptides containing α,α-disubstituted α-amino acids, derived from the crystal structures of 28 compounds, are reviewed. In particular, the sensitivity of peptide conformation to the geometry of these unusual amino acids is underlined. We also consider possible future directions of research, which, we hope, will result in a complete understanding of the structures adopted by peptaibol antibiotics.     

Fuzzy set ordination and classification of Serengeti short grasslands,Tanzania

Abstract. Species abundance data from 32 representative stands are used to evaluate the vegetation in the heavily grazed Serengeti short grasslands. The abundant species are: Kyllinga nervosa, Sporobolus ioclados, S. kentro-phyllus and Eustachys paspaloides, all occurring in elevated areas, and Hypoestes forskalei, which is found in the drainage areas. Numerical classification and fuzzy set ordination revealed four main grassland communities associated with a topographic gradient. The communities are considered distinct since their niches, as computed in the community and environmental fuzzy system space are not overlapping. Leaching, erosion and animal disturbance effects correlated with the topographic gradient are found to determine species composition and overall community structure in the grasslands.