N-terminal anthranoyl-phenylalanine derivatives as CCK1 receptor antagonists: the final approach.

Starting from our lead compound, VL-0395, an anthranilic acid based CCK1 receptor antagonist, and following the well established "step by step" lead investigation strategy, we describe the final step of the anthranilic acid N-terminal optimization. Improvements for both affinity and selectivity towards CCK1 receptors have been accomplished through introduction of the fluoro substituent at C-5 and C-7 position of the indole ring together with the appropriate configuration of the aminoacidic chiral center.

Synthesis of N-terminal substituted anthranilic acid dimer derivatives for evaluation on CCK receptors.

A series of new N-substituted anthranilic acid dimer derivatives having a C-terminal Phe residue was synthesized and evaluated for their affinity for CCK receptors. These compounds resulted from a blended approach based firstly on the use of an alternative substructure embedded within asperlicin and secondly on the derivatization of this template with substituents chosen considering the C-terminal primary structure of the endogenous ligand. Although these compounds exhibited a regnylogical-type organization similar to that of CCK-4, they are characterized by about 1000-fold greater affinity for CCK-A receptor than the C-terminal tetrapeptide.

Synthesis of new anthranilic acid dimer derivatives and their evaluation on CCK receptors.

We have described previously an innovative bond disconnection strategy of asperlicin, a naturally occurring CCK receptor antagonist, leading to anthranilic acid dimer and tryptophan synthons. We have also demonstrated that when the tryptophan residue is connected to the C- or N-terminal sides of the anthranilic acid dimer, compounds with similar micromolar CCK-A receptor affinities are obtained. In order to investigate the binding effects of different N-terminal substitution, in this paper we describe a new series of anthranilic acid dimer derivatives, characterized by the presence of the tryptophan residue in the C-terminus of the dimer. Among the compounds synthesized, the N-1H-indol-3-propionyl derivative exhibited an improved, at the micromolar range, affinity for the CCK-A receptor in comparison to that of either, the N-unsubstituted derivative and asperlicin. The lead compound emerging from this key step of our investigation represents the new starting point for the development of a new class of CCK-A receptor ligands.

C-terminal anthranoyl-anthranilic acid derivatives and their evaluation on CCK receptors.

A series of C-terminal anthranoyl-anthranilic acid derivatives arising from a strict bond disconnection approach of asperlicin were synthesized and examined for their CCK receptor affinities. These compounds represent the second step of our investigation directed toward the search for alternative substructures of asperlicin as a starting point for the development of a new class of CCK ligands. The obtained micromolar affinities for CCK-A rather than CCK-B receptor confirm that the anthranilic acid dimer represents a useful template for the development of selective CCK-A receptor ligands.

Tubular structures in cells of cucumovirus-infected Nicotiana glutinosa leaves.

Peculiar tubular structures about 250 nm in diameter were found in cells of Nicotiana glutinosa leaves infected with a cucumovirus strain isolated from field-grown tobacco in southwest Slovakia.

Intraspecies variability in transmission efficiency of stylet-borne viruses by the pea aphid (Acyrthosiphon pisum).

The efficiency of bean yellow mosaic virus (BYMV; Potyvirus group) tranasmission from pea to pea plants by 36 clones of the pea aphid (Acyrthosiphon pisum) was studied. The efficiency of the clones varied; it was not related to the aphid colour form (green, red or yellow) or the origin of the clone (host plant, geographic area). With alfalfa mosaic virus, the virus-vector relationships concerning transmission efficiency were, in general, similar to those found with BYMV. The behaviour of the clones to the circulative pea enation mosaic virus was, however, different.

Iodopeptides from human thyroglobulin.

Human thyroglubulin labelled in vivo by 125I was purified from eight different thyroid glands including normal thyroid tissue, thyrotoxic goitre and euthyroid multinodular goitre. The purified protein was cleaved with cyanogen bromide (CNBr) and the resulting peptides were separated by column chromatography and ion exchange chromatography. Reproducible elution profiles of both protein and iodine were obtained. However, the distribution of iodine depended on the iodine content of the intact thyroglobulin. Small CNBr peptides seemed to be preferentially iodinated, but with a limited capacity. With higher degrees of iodination, larger peptides became richer in iodine. This suggests sequential iodination of the thyroglobulin molecule. The mixture of small peptides was digested by trypsin. Two iodopeptides were identified in this material by peptide mapping and they had identical migration in thyroglobulins of different origin. One of them was purified by ion exchange chromatography and high voltage electrophoresis. Analogous amino acid composition was obtained for the iodopeptide purified from two different thyroglobulins. The data indicates that thyroglobulin iodination occurs in specific portions of the polypeptide chain and probably in a sequential manner.