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M Lebl

Publications and source records attributed to M Lebl.

At least 55 records · Page 3Linked to original sources
PubMed1990

Conformationally restricted analogs of oxytocin; stabilization of inhibitory conformation.

Analogs of oxytocin containing tetrahydroisoquinoline carboxylic acid (Tic) of L or D configuration in position 2 were synthesized and their biological activities were tested. Both analogs showed negligible agonist activity in uterotonic, galactogogic, and pressor assays, but they are in vitro uterotonic inhibitors. In comparison with oxytocin analogs containing L- or D-phenylalanine in position 2, the analog with the D-configuration of the conformationally fixed aromatic residue has significantly increased inhibitory activity which suggests that the proper conformation for the interaction with the receptor, but not for its activation, was stabilized. 1H NMR and CD studies, supported by theoretical calculations, suggest that the conformational properties of the analog containing D-tetrahydroisoquinoline carboxylic acid are similar to those of [2-D-phenylalanine]oxytocin.

Animals↗
PubMed1989

Melanin concentrating hormone analogues: contraction of the cyclic structure. II. Antagonist activity.

Asp-Thr-Met-Arg-Cys-Met-Val-Gly-Arg-Val-Tyr-Arg-Pro-Cys-Trp-Glu-Val, melanin concentrating hormone (MCH), is a cyclic hormone possessing both MCH-like (melanin granule aggregating effect) and melanocyte stimulating hormone (MSH)-like (melanin granule dispersing effect) activities. Nine ring-contracted analogues were synthesized and characterized for their melanotropic activity on the fish (Synbranchus marmoratus) and frog (Rana pipiens) bioassays. In most cases, these analogues were totally devoid of MCH-like agonist activity, demonstrating the essential role of the disulfide bridge between residues 5 and 14 of the hormone. [Ala5, Cys10]MCH, for example, was totally devoid of MCH-like activity. This analogue, like alpha-MSH, however, antagonized the melanosome aggregating actions of MCH on fish melanocytes. The antagonistic activity of the analogue, like that of alpha-MSH, was Ca2+-dependent. Evidence suggested that this antagonism of MCH activity was related to the intrinsic MSH-like activity of the analogue. These results suggest that MCH and alpha-MSH may be structurally and, therefore, evolutionarily related.

Animals↗
PubMed1989

Melanin concentrating hormone. III. Melanin concentrating hormone (MCH): the message sequence.

Melanin concentrating hormone (MCH) is a heptadecapeptide synthesized by the hypothalamus and secreted by the neurohypophysis of the teleost pituitary gland. MCH stimulates melanosome aggregation within teleost melanocytes but also exhibits MSH-like (melanosome dispersing) activity on tetrapod (frog and lizard) melanocytes. We have synthesized a number of MCH analogues to determine the essential features of the primary structure necessary to stimulate either melanosome aggregation or dispersion in fish or tetrapod melanocytes, respectively. An analysis of the potencies and actions of these analogues on vertebrate melanocytes is provided and demonstrates that the two activities have different structural requirements.

Amino Acid Sequence↗
PubMed1989

Melanocyte stimulating hormone and melanin concentration hormone may be structurally and evolutionarily related.

Two melanotropic peptides, melanin concentration hormone (MCH) and alpha-melanocyte stimulating hormone (alpha-MSH), exert opposing actions on melanosome (melanin granule) movements within teleost pigment cells, melanocytes (melanophores). MCH stimulates melanosome aggregation to the cell center whereas alpha-MSH stimulates pigment organelle dispersion out into the dendritic processes of the melanocytes. The actions of alpha-MSH are dependent upon extracellular calcium (Ca2+), whereas those of MCH are actually enhanced in the absence of the cation. At high concentrations (10(-5)-10(-8) M) MCH also exhibits MSH-like activity (autoantagonism), an effect which is abolished in the absence of Ca2+. Therefore, MCH exhibits MCH-like as well as MSH-like activity depending on the presence or absence of extracellular Ca2+. An analogue of MCH, [Ala5, Cys10]MCH, has been synthesized which is totally devoid of MCH activity but still exhibits MSH-like activity. These results suggest that the two melanotropic peptides share some component of structural similarity and may be evolutionarily related.

Amino Acid Sequence↗
PubMed1989

Analogs of oxytocin containing a pseudopeptide Leu-Gly bond of cis and trans configuration.

Analogs of deamino-oxytocin wherein the Leu-Gly peptide bond has been replaced by a tetrazole moiety or by a double bond of trans configuration were synthesized and their biological activities evaluated. Trans double bond was found to be the most appropriate substitution for the amide bond (uterotonic activity 24% of the deamino-oxytocin). In the case of all three analogs low but prolonged galactogogic activity was found and the ratio of uterotonic in vitro and in vivo activity was surprisingly high (ranging from 4.5 to 20).

Animals↗
PubMed1988

Melanin concentrating hormone analogues: contraction of the cyclic structure. 1. Agonist activity.

Melanin concentrating hormone (MCH) is a heptadecapeptide, Asp-Thr-Met-Arg-Cys-Met-Val-Gly-Arg-Val-Tyr-Arg-Pro-Cys-Trp-Glu-Val, which is synthesized in the hypothalamus and secreted by the neurohypophysis of teleost fishes. This hormone exhibits both MCH-like as well as alpha-MSH (alpha-melanocyte stimulating hormone) like activity. We have examined the role of the disulfide bond for the two contrasting melanotropic activities of MCH. Nine analogues of the parent peptide were synthesized and characterized for biological activity. The disulfide ring was contracted from the 5-14 to the 7-14, 8-14, and 10-14 residues with concomitant substitution of alanine for Cys at position 5 in each of the heptadecapeptides. Similar substitutions were made in a series of MCH analogues. In addition, the following cyclic peptides also were synthesized: [Cys7]MCH, [Cys8]MCH, and [Cys10]MCH. The fish-skin bioassay is sensitive to MCH at a concentration of 10(-12) M. All ring-contracted analogues were inactive at 10(-6) M or lower concentrations; less than 1/1,000,000 compared to MCH (1.0) except [Ala5,Cys8]MCH (0.0008; 1/1250), [Cys10]MCH (0.000 09; 1/10,000), and [Cys8]MCH (0.000 001; 1/1,000,000). In the frog-skin bioassay, [Ala5,Cys10]MCH, although lacking MCH-like activity in the fish-skin bioassay, was equipotent to MCH in its alpha-MSH-like component of activity. Most other analogues were either inactive or much less active than MCH in stimulating melanosome dispersion. These results demonstrate that the disulfide bond between positions 5 and 14 is essential for the MCH-like activity since contraction of the ring generally leads to inactive peptides. Contraction of the disulfide bridge does not, however, have as great an effect on the MSH-like activity of MCH.

Animals↗
PubMed1987

Analogs of oxytocin containing a modified peptide bond.

Analogs of deamino-oxytocin and deamino-oxypressin containing a CH2-NH group instead of an amide bond between positions 8 and 9 were synthesized. All tested compounds exhibit significantly lowered biological activities.

Animals↗
PubMed1987

Effect of threonine in position 4 in oxytocin and vasotocin analogs on the time course of uterotonic response.

The substitution of glutamine by threonine in position 4 of oxytocin, deamino-oxytocin, deamino-1-carba-oxytocin, and deamino-6-carba-oxytocin was found to increase the elimination rate of all analogs examined from the uterine receptor compartment in rat. However, this substitution was without any effect on the time course of uterotonic response in the case of vasotocin and deamino-vasotocin. These results suggest that the topological relationships of the 4 and 8 positions may show an important effect on elimination rate of oxytocin and vasotocin analogs from the rat uterine compartment.

Animals↗
PubMed1984

Cyclic melanotropins. Part VII: Modified ring structures--synthesis and biological activity.

The highly potent cyclic analogue of alpha-MSH, Ac-[Cys4,Cys10]-alpha-MSH4-13-NH2, was structurally modified in position 4. Four analogues were prepared and their biological activities in the in vitro frog and lizard skin bioassays were determined. It was shown that removing the terminal acetylamino group to give [Mpa4,Cys10]-alpha-MSH4-13-NH2 resulted in little change in the biological activity, but a change in the stereochemistry of cysteine in position 4 to give Ac-[D-Cys4,Cys10[-alpha-MSH4-a3-NH2 led to a small decrease of activity in both bioassays. Decreasing the size of the intramolecular ring by removing one methylene group to give [Maa2,Cys10]-alpha-MSH4-13-NH2, resulted in an analogue with lower activities in both assays (about 3 times in the lizard and 500 times in the frog), and increasing the size of the righ by methylene group to give Ac-[Hcy4,Cys10]-alpha-MSH4-13-NH2 led to much lower activities in the lizard system and similar effects were seen upon decreasing the ring size in the frog skin assay.

Amino Acid Sequence↗
PubMed1984

Nacartocin--analogue of oxytocin with enhanced natriuretic properties: natriuretic and hemodynamic characteristics.

Nacartocin, [2-p-ethylphenylalanine]deamino-6-carba-oxytocin, is almost three times more potent than oxytocin as a natriuretic agent. The natriuretic effect is mainly due to the inhibitory action of the peptide on tubular sodium resorption. Nacartocin decreased the blood pressure of anesthetized rats by the decrease of the total peripheral resistance which was greater than that observed after oxytocin administration. In conscious rats, Nacartocin caused a slight but prolonged increase of blood pressure.

Animals↗
PubMed1980

Effect of some oxytocin analogues on natriuresis in rats.

Non-anaesthetized rats were used for studying the relationship between the amount of sodium excreted and structural modifications of oxytocin molecule. Any change performed in position 4 (i.e. the glutamine residue) resulted in a decrease of natriuretic activity as compared to that of oxytocin. The analogues with modifications in the amino-terminal part of the molecule (e.g. substitution of the amino group in position 1 by hydrogen, or of the disulfide bond by a thioether group) resulted in a higher natriuretic effect than oxytocin.

Animals↗
PubMedDate not supplied

Inclusion volume solid-phase synthesis.

Solid-phase synthesis of peptides was carried out using only the volume of the solvent included in the swollen solid-phase resin heads (inclusion volume synthesis). This approach enables (i) the use of higher concentrations of activated amino acids, resulting in increased coupling rates, (ii) drastically decreased consumption of solvents, and (iii) the construction of multiple peptide synthesizers having virtually no reaction vessels.

Amino Acids↗
PubMedDate not supplied

Melanin concentrating hormone (MCH): structure-function aspects of its melanocyte stimulating hormone-like (MSH-like) activity.

Melanin concentrating hormone (MCH) is a heptadecapeptide, Asp-Thr-Met-Arg-Cys-Met-Val-Gly-Arg-Val-Tyr-Arg-Pro-Cys-Trp-Glu-Val, synthesized in the brain and secreted from the pars nervosa of teleost fish. This hormone stimulates melanosome (melanin granule) aggregation within integumental melanocytes of fishes but, in contrast, stimulates melanosome dispersion within tetrapod (frog and lizard) melanocytes. We determined the message sequence of the primary structure of MCH which is responsible for its MSH-like component of activity. Removal of the N-terminal amino acid results in an almost total loss of MSH-like activity. The C-terminal amino acid is also essential for full MSH-like activity since the analogue, MCH(1-16), is about 100 times less active than MCH. Therefore, the entire heptadecapeptide sequence of MCH appears to contribute to the MSH-like activity of MCH. Ring-contracted analogues (e.g., [Ala5, Cys10]MCH) of MCH are almost devoid of any melanosome aggregating (MCH-like) activity but generally possess considerable or as great an MSH-like activity as MCH. Racemization of MCH by heat-alkali treatment drastically reduces the MCH-like activity of MCH, but does not enhance the MSH-like activity of the hormone.

Amino Acid Sequence↗
PubMedDate not supplied

Evaluation of gaseous hydrogen fluoride as a convenient reagent for parallel cleavage from the solid support.

We have tested the limits of gaseous hydrogen fluoride as an agent for parallel detachment of organic molecules from the solid support. Peptides were chosen as relatively sensitive models for this reaction. Acid-catalyzed amide bond hydrolysis, side chain modification (tryptophan and other unnatural amino acids) by the protecting group residues as well as dehydration of serine and asparagine was followed. The technique of cleavage of side chain protection prior to the resin cleavage has given satisfactory results. Two-step deprotection and cleavage from benzhydrylamine resin by TFA and HF was compared to the deprotection and cleavage by TFA from Knorr resin.

Amino Acid Sequence↗
PubMedDate not supplied

Evaluation of cotton as a carrier for solid-phase peptide synthesis.

Cotton as a new support for the solid-phase synthesis of peptides was evaluated under the conditions of both Boc/Bzl and Fmoc/But strategy. Syntheses of peptides containing only bifunctional amino acids gave comparable results, but peptides containing trifunctional amino acids are clearly advantageously synthesized using the Fmoc approach. The comparison of cotton with other planar carriers (paper or polypropylene membranes) and with classical pellicular ones has shown practical applicability of cotton as the replacement of more sophisticated carriers. N-Methylimidazole was shown to be the optimal acylation catalyst for the modification of the cellulose carrier. Stability of the ester bond to the cotton was studied and shown to be adequate for the syntheses of small to medium size peptides. A relatively low level of substitution of cotton carrier in connection with its ability to soak the solvent was used for the complete elimination of a synthetic vessel. Couplings can be performed by wetting the carrier with the coupling solution, and all solvents can be removed either by squeezing it together with a porous material (paper) or by centrifugation. This leads to a significant decrease of solvent consumption. The efficiency of solvent elimination by centrifugation was demonstrated by the synthesis of model peptide ACP 65-74 in which only one wash between coupling and deprotection and between deprotection and coupling was used and which afforded the product of the same quality as the product synthesized using the standard protocol. Bromophenol blue monitoring has been proven as the optimal way of monitoring the acylation reaction progress. Peptides directly bound to cotton were shown to be useful in enzyme-linked immunosorbent assay tests.

Acylation↗