Offset rate of action of muscarinic antagonists depends on their structural flexibility

Summary Time course measurements of the action of muscarinic antagonists were performed in the spontaneously beating carp atrium. Several high affinity drugs, which embody the quinuclidine structure were examined. The structural flexibility of these molecules was reflected in the dissociation of the drugs from the muscarinic receptor. The dissociation of rigid drugs was very much prolonged as compared to flexible drugs of the same affinity.We thank Prof. S. Lifson for helpful discussion and Mrs M. Bendikovsky for technical assistance. This work was supported by a USA-Israel Binational Science Foundation (BSF-Jerusalem) grant to Y. Lass.     

The rate of action of cyclic ammonium and sulfonium analogues of acetylcholine.

The rate of action of cyclic acetylcholine analogues in the 4-acetoxypiperidine and 4-acetoxythiacyclohexane series has been determined by using the isolated left guinea-pig atrium. The kinetic data obtained has been correlated with the experimental ED50-value on the muscarinic receptor.     

Dependence on the lipophilicity of maleimide derivatives in their inhibitory action upon chemotaxis in neutrophils.

Modification of polymorphonuclear neutrophils by a series of maleimide derivatives with various degrees of lipophilicity and hydrophilicity indicated that hydrophilic reagents had little effect on chemotaxis, whereas the degree of the inhibitory effect of lipophilic reagents on the chemotaxis was parallel to the degree of their lipophilicity.     

The rate of action of cyclic ammonium and sulfonium analogues of acetylcholine

Summary The rate of action of cyclic acetylcholine analogues in the 4-acetoxypiperidine and 4-acetoxythiacyclohexane series has been determined by using the isolated left guinea-pig atrium. The kinetic data obtained has been correlated with the experimental ED₅₀-value on the muscarinic receptor.Structure and Conformation Activity Relationships of Cyclic Acetylcholine Analogues.VI.We thank the German Research Association for supporting this work, and Mrs Ch. Röttger for her valuable assistance in carrying out the investigations.     

The investigation of the action of ultrasound on some proteid substances. Part II. The action of ultrasound on diastase

Zusammenfassung Die Ultraschallwirkung auf Diastase wurde an deren Aktivitäts- und pH-Änderung untersucht. Verschieden lang beschallte, 0.5% ige wässerige Diastaselösungen ergaben stufenweises und regelmässiges Absinken der Aktivitäten und pH-Werte.

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Part I: Bull. Soc. chim. Belgrade (in press).     

The Sushi peptides: structural characterization and mode of action against Gram-negative bacteria

The compositional difference in microbial and human cell membranes allows antimicrobial peptides to preferentially bind microbes. Peptides which specifically target lipopolysaccharide (LPS) and palmitoyl-oleoyl-phosphatidylglycerol (POPG) are efficient antibiotics. From the core LPS-binding region of Factor C, two 34-mer Sushi peptides, S1 and S3, were derived. S1 functions as a monomer, while S3 is active as a dimer. Both S1 and S3 display detergent-like properties in disrupting LPS aggregates, with specificity for POPG resulting from electrostatic and hydrophobic forces between the peptides and the bacterial lipids. During interaction with POPG, the S1 transitioned from a random coil to an α-helix, while S3 resumed a mixture of α-helix and β-sheet structures. The unsaturated nature of POPG confers fluidity and enhances insertion of the peptides into the lipid bilayer, causing maximal disruption of the bacterial membrane. These parameters should be considered in designing and developing new generations of peptide antibiotics with LPS-neutralizing capability. Received 2 October 2007; received after revision 2 November 2007; accepted 4 December 2007 J. L. Ding, B. Ho: Co-senior authors.     

Non-host-selective fungal phytotoxins: Biochemical aspects of their mode of action

During the last decade increasing attention has been directed towards the biochemical mechanisms responsible for the biological activity of phytotoxins. Studies on the mode of action of some non-host-selective phytotoxins, some following on from previous observations, have demonstrated a very specific interaction with particular components of the cell machinery, and have suggested the possible use of these phytotoxins as tools for the investigation of important biochemical processes. This review article reports and discusses results of studies carried out in the 1980s with seven non-host-selective fungal toxins: brefeldin A, cercosporin,Cercospora beticola toxin, fusicoccin, ophiobolins, tentoxin, and zinniol. Each of these interferes with the life of the host by interacting with a different biochemical target.     

Dependence on the lipophilicity of maleimide derivatives in their inhibitory action upon chemotaxis in neutrophils

Summary Modification of polymorphonuclear neutrophils by a series of maleimide derivatives with various degrees of lipophilicity and hydrophilicity indicated that hydrophilic reagents had little effect on chemotaxis, whereas the degree of the inhibitory effect of lipophilic reagents on the chemotaxis was parallel to the degree of their lipophilicity.This work was supported in part by a grant-in-aid for Scientific Research (No.267043) from the Ministry of Education, Science and Culture, Japan, awarded to T.Y.     

An evaluation of apomorphine action on doapminergic receptors.

The controversial literature reports leave open a question whether apomorphine (APO) and dopamine (DA) share a common receptor? After careful evlauation of the arguments, both for and against, about direct action of APO on DA receptor we propose that rigid molecules like APO hold trans-cisoid conformation and preferably interact with the pre-synaptic DA receptors while ADTN (2-amino-6,7-dihydroxy, 1,2,3,4-tetrahydrxonaphthalene) incorporates trans-transcoid conformation and primarily acts on post-synpatic DA receptors. Dopamine, by virtue of its molecular flexibility, can act on both the receptors.     

Dissociation constants of 4-acetoxy-piperidines and -thiacyclohexanes at the muscarinic receptor.

The dissociation constants (KA) and the relative intrinsic efficacies (e) of 4-acetoxy-piperidines and -thiacyclohexanes were determined on the guinea-pig isolated left atrium. The differences in the muscarinic potencies are associated with differences in affinities and efficacies, respectively.     

Effect of cortexolone on the feedback action of dexamethasone.

Cortexolone in a dose of 1 mg/100 g body wt., administered to rats prior to dexamethasone, prevented dexamethasone from suppressing stress-induced ACTH-release without interfering with the effect of dexamethasone on the resting plasma corticosterone level.     

Effects of dopamine antagonists on snail locomotion

Summary Dopamine antagonists which affect the ergometrine-sensitive type of dopamine receptors produce characteristic motor disorders in a land snail,Helix pomatia L.Acknowledgment. We are grateful to Dr L. Hiripi for valuable suggestions and Dr I. Varanka for help in photography.     

Number of glucocorticoid receptors in lymphocytes and their sensitivity to hormone action

The study demonstrated a decreased level of glucocorticoid receptors (GR) in peripheral blood lymphocytes from hypercholesterolemic subjects, and an elevated level in patients with acute myocardial infarction. In the lymphocytes with a high GR number, dexamethasone inhibited [3H]-thymidine and [3H]-acetate incorporation into DNA and cholesterol, respectively, in the same manner as in the control cells. On the other hand, a decreased GR number resulted in a less efficient dexamethasone inhibition of the incorporation of labeled compounds. These data showed that the sensitivity of lymphocytes to glucocorticoids changed only with a decrease of GR level.     

Haemolytic activity and action on the surface tension of aqueous solutions of synthetic melittins and their derivatives

Zusammenfassung Melittin I und II wurden auf verschiedenen Wegen durch Fragmentkondensation synthetisiert. Beide Verbindungen sowie ihre Teilsequenzen wurden auf ihre hämolytische Aktivität und auf ihre Wirkung auf die Oberflächenspannung wässriger Lösungen untersucht. Die Ergebnisse zeigen, dass neben der Oberflächenaktivität noch andere Strukturmerkmale für die hämolytische Aktivität verantwortlich sind.

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Peptide Syntheses XLVII, 3rd Communication on melittin.