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Biomedical subjects

M Bodanszky

Publications and source records attributed to M Bodanszky.

At least 37 records · Page 2Linked to original sources
PubMed1982

Selective modification of the ability of cholecystokinin to cause residual stimulation of pancreatic enzyme secretion.

In the C-terminal heptapeptide of cholecystokinin (-Tyr(SO3H)-Met-Gly-Trp-Met-Asp-Phe-NH2), replacing the aspartic acid residue by beta-aspartic acid did not alter the ability of the peptide to cause stimulation, desensitization, or residual stimulation of enzyme secretion from dispersed pancreatic acini. Replacing the tyrosine sulfate residue by hydroxynorleucine sulfate did not alter the ability of the heptapeptide to cause stimulation or desensitization, but caused a 50-fold decrease in the potency with which the peptide caused residual stimulation of enzyme secretion. These findings suggest that a modification of the N-terminal region of cholecystokinin heptapeptide, which does not alter the ability of the peptide to bind to its receptor on pancreatic acini and by so doing cause stimulation and desensitization of enzyme secretion, can increase the rate at which the bound peptide dissociates when the acini are washed and reincubated. This increased dissociation is reflected by a reduction in the potency with which the peptide causes residual stimulation of enzyme secretion.

Amylases↗
PubMed1982

Allomalformin.

In an attempt to find explanation for the initial erroneous sequence assignment for malformin, a sequence-isomer of the natural product, 3-isoleucine-5-valine malformin or briefly "allomalformin" that on partial acid hydrolysis could have given rise to misleading fragments, was synthesized and compared with both natural and synthetic preparations of malformin. Allomalformin is identical to the parent microbial peptide (malformin A, or briefly malformin) with respect to biological activity and conformation (ORD and CD spectra) and is indistinguishable from it by high pressure liquid chromatography. Yet, the two isomers have slightly different Rf values on thin-layer chromatograms and by this method no allomalformin could be detected in samples of the natural product. On the other hand both high pressure liquid chromatography and thin-layer chromatography demonstrated the presence of the lower homolog, 5-valine malformin, in the samples examined. On partial acid hydrolysis this natural analog should liberate Val-Cys, while Cys-Val forms from malformin itself. Similarly, the corresponding desthio cyclopentapeptides should give rise to Val-Ala and Ala-Val respectively; the former being more resistant to further hydrolysis persists in the partial hydrolysates. The presence of Val-Cys in partial hydrolysates of malformin and of Val-Ala in the partial hydrolysates of desthiomalformin, both originating from the accompanying lower homolog rather than from malformin itself, is likely to have led to the postulation of the erroneous Cys-Val-Cys partial sequence.

Amino Acid Sequence↗
PubMed1981

The importance of the amino acid in position 32 of cholecystokinin in determining its interaction with cholecystokinin receptors on pancreatic acini.

In the C-terminal heptapeptide of cholecystokinin, replacement of the penultimate residue, aspartic acid, by beta-alanine caused a 300-fold decrease in the potency with which the peptide stimulated enzyme secretions, whereas replacement by glutamic acid caused a 1000-fold decrease in potency. The beta-alanine-substituted peptide was approximately ten times more potent when the n terminus was blocked with t-butyloxycarbonyl than when it was blocked with benzyloxycarbonyl, and the glutamic acid-substituted peptide was approximately twice as potent when the N terminus was blocked with t-butyloxycarbonyl than when it was blocked with benzyloxycarbonyl. Changes in the ability of the peptide to stimulate amylase secretion were accompanied by corresponding changes in the ability of the peptide to inhibit binding of 125I-labeled cholecystokinin. The magnitude of stimulation of enzyme secretion caused by a maximally effective peptide concentration was the same with each analogue as it was with the unaltered peptide. Replacing the aspartyl residue by beta-alanine or glutamic acid or replacing the N-terminal t-butyloxycarbonyl moiety by benzyloxycarbonyl caused an equivalent decrease in the ability of the peptide to stimulate enzyme secretion and its ability to cause residual stimulation of enzyme secretion. In contrast, the N-terminal desamino analogue of cholecystokinin heptapeptide was ten times less potent than the unaltered peptide in stimulating amylase secretion, but 100 times less potent than the unaltered peptide in causing residual stimulation of enzyme secretion.

Alanine↗
PubMed1981

Synthesis of 8-L-tryptophan-oxytocin and determination of one of its conformational parameters.

The hormone analog 8-L-tryptophan-oxytocin was synthesized in solution by stepwise chain lengthening from the C-terminal residue. Active esters of 9-fluorenylmethyloxycarbonyl (Fmoc)-amino acids were used for the incorporation of individual residues and thereby exposure to the tryptophan-containing intermediates both to acid conditions and to alkylation could be avoided. In a parallel experiment the parent compound, oxytocin, was prepared similarly. The final products were purified by countercurrent distribution. The presence of tyrosine (donor) and tryptophan (acceptor) in the chain was used for the measurement of the average intramolecular Tyr2-Trp8 distance by evaluation of intramolecular resonance energy transfer between their fluorescent side chains. Since the 8-L-tryptophan analog has high affinity for oxytocin receptors, it is reasonable to assume that its conformation is similar to that of the parent molecule and that in the latter the leucine-tyrosine distance is of about the same length. The distance of 13.5 Ao between the side chains of tyrosine and tryptophan measured in aqueous solution is compatible with the Tyr2-Leu8 distance determined with molecular models built according to the proposals of Walter for the biologically active conformation of oxytocin.

Amino Acid Sequence↗
PubMed1980

The importance of the amino acid in position 27 of cholecystokinin in determining its biological activity on pancreatic acini.

We tested the synthetic C-terminal heptapeptide of cholecystokinin, which has the same biologic activity as cholecystokinin, and various synthetic analogs of the C-terminal heptapeptide for their abilities to increase amylase secretion from dispersed acini prepared from guinea-pig pancreas. We found that altering the chemical character of the amino acid in position 27 altered the potency with which the peptide stimulated amylase secretion but did not alter the efficacy of the peptide. We also found that, in the amino acid in position 27, the major function of the side-chain seems to be to position to the sulfate ester group at a proper distance from the backbone of the peptide chain, whereas the chemical structure of the side-chain per se seems to be of relatively minor importance.

Amino Acid Sequence↗
PubMed1980

Synthesis and some pharmacological properties of [8-L-tryptophan]oxytocin.

Condensation of (tert-butyloxycarbonyl)tocinoic acid with L-prolyl-L-tryptophylglycinamide produced the Boc derivative of a nonapeptide (disulfide) which on deprotection afforded [8-L-tryptophan]oxytocin. In assays on the rat uterus in vitro and in vivo the new analogue acts as both an agonist and an antagonist. The duration of both actions is prolonged.

Animals↗
PubMed1980

Importance of the amino acid in position 15 of VIP and secretin in influencing their interactions with membrane receptors on pancreatic acinar cells.

To explore the importance of the charge of the amino acid in position 15 in influencing the apparent affinities of VIP and secretin for their receptors on pancreatic acinar cells, we tested the synthetic C-terminal 23-peptide fragment of secretin (S5-27) and two analogues containing substitutions in position 15 for their abilities to interact with secretin-preferring and VIP-preferring receptors on pancreatic acinar cells. In inhibiting the increase in cyclic AMP caused by VIP acting through the VIP-preferring receptors, 15-Lys-S5-27 was equipotent with 15-Asn-S5-27, and these analogues were significantly more potent than S5-27. In inhibiting the increase in cyclic AMP caused by secretin acting through the secretin-preferring receptors, S5-27 was equipotent with 15-Asn-S5-27, and these peptides were significantly more potent than 15-Lys-S5-27. These findings indicate that the affinities of these 23-peptides for the VIP-preferring receptors and for the secretin-preferring receptors were influenced primarily by the absence of a particular charge in position 15 but not by the presence of the opposite charge.

Amino Acid Sequence↗
PubMed1980

Cholecystokinin (pancreozymin). Synthesis and properties of the N alpha-acetyl-derivative of cholecystokinin 27-33.

The acetyl-derivative of the biologically active C-terminal 7-peptide portion of cholecystokinin (CCK), N-acetyl-O-sulfate-L-tyrosyl-L-methionyl-glycyl-L-tryptophyl-L-methionyl-L-aspartyl-L-phenylalanine amide was prepared by the condensation of 2-peptide segments with 1-isobutyloxycarbonyl-2-isobutyloxy-1,2-dihydroquinoline as coupling reagent. The N-terminal residue, tyrosine was incorporated by the active ester method. The same 7-peptide was prepared also by stepwise chain-lengthening, starting with the C-terminal residue. The 9-fluorenylmethyloxycarbonyl group was applied for the protection of alpha-amino functions. In the release of amylase from acinar cells of the pancreas of guinea pigs, the acetyl-7-peptide amide was about 3 times more potent than CCK 27-33 and equal in potency to CCK 26-33. The new derivative strongly stimulated the contraction of the in situ guinea pig gall bladder.

Amino Acid Sequence↗
PubMed1979

Interaction of secretin5-27 and its analogues with hormone receptors on pancreatic acini.

The C-terminal tricosapeptide of secretin (S5-27) and two analogues, one with asparagine replacing aspartic acid in position 15 (15-Asn-S5--27) and one with lysine replacing aspartic acid in position 15 (15-Lys-S5-27) were tested for their abilities to interact with hormone receptors on pancreatic acinar cells. In interacting with the receptors which prefer vasoactive intestinal peptide (vasoactive intestinal peptide-preferring receptors), the apparent affinity of 15-Asn S5-27 was equal to that of 15-Lys-S5-27 and was greater than that of S5-27. In interacting with secretin-preferring receptors, the apparent affinity of 15-Asn-S5--27 was equal to that of S5-27 and was greater than that of 15-Lys-S5-27. In interacting with the secretin-preferring receptors each of the secretin fragments was approximately 2% as effective as secretin in causing an increase in cellular cyclic AMP. None of these fragments was able to cause a detectable increase in cyclic AMP mediated by the vasoactive intestinal peptide-preferring receptors. The dose vs. response curves for the action of secretin and vasoactive intestinal peptide on cellular cyclic AMP and on amylase secretion as well as the pattern of effects of secretin fragments on these actions indicated that the increase in amylase secretion caused by vasoactive intestinal peptide and secretin is mediated exclusively by the vasoactive intestinal peptide-preferring receptors. Furthermore, occupation of approximately 50% of the vasoactive intestinal peptide-preferring receptors is sufficient to cause maximal stimulation of amylase secretion.

Amylases↗
PubMed1978

A ureido group containing analogue of oxytocin comprising eight amino acid residues.

A new analogue of oxytocin was constructed from L-tyrosyl-L-isoleucyl-L-glutaminyl-L-asparaginyl-L-lysyl-L-prolyl-L-leucyglycinamide. Reaction of this 8-peptide amide with di-p-nitrophenyl carbonate yielded a cyclic compound, in which the -CH2SSCH2-bridging portion of oxytocin formed by the oxidative linking of the two cysteine side chains was replaced by the -CH2CH2CH2CH2-group of lysine, while the epsilon-NH2 group of the same residue took the place of the alpha-CH of cysteine-1. The N-terminal amino group of oxytocin, which is not necessary for its hormonal activities, was omitted. The new analogue, referred to as [1,6-Nepsilon-carbonyl-L-lysine]oxytocin, possessed a rat uterotonic activity in vitro of 3.9 +/- 0.3 units/mg, less than 0.5 unit/mg of rat antidiuretic activity, and caused a marked tachyphylaxis in the rat pressor assay. Moreover, the analogue was a strong competitive inhibitor, with a pA2 value of 7.27 +/- 0.13 of the oxytocin induced vasodepressor response in chickens.

Animals↗
PubMed1978

Cholecystokinin (pancreozymin). 4. Synthesis and properties of a biologically active analogue of the C-terminal heptapeptide with epsilon-hydroxynorleucine sulfate replacing tyrosine sulfate.

The influence of tyrosine O-sulfate, the 27th residue in the sequence of cholecystokinin (pancreozymin) (CCK-PZ), on the contraction of gall bladder of guinea pigs and on the release of amylase in isolated pancreatic cells of the same animal was studied with an analogue of the biologically active C-terminal heptapeptide, CCK-PZ-(27--33). In the new analogue, tyrosine O-sulfate was replaced by epsilon-hydroxynorleucine O-sulfate. The synthetic peptide was found a full agonist in these tests, not quite as potent as the unaltered heptapeptide, but much more active than the previously prepared and studied serine O-sulfate containing analogue. Thus, the distance of the sulfate ester group from the peptide backbone has a major influence on the biological activity of CCK-PZ.

Amino Acid Sequence↗
PubMed1978

Determination of the intramolecular tyrosine-tryptophan distance in a 7-peptide related to the C-terminal sequence of cholecystokinin.

The solution conformation of a 7-peptide with the C-terminal sequence of cholecystokinin was investigated by evaluation of intramolecular resonance energy transfer between tyrosine (donor) in position 1 and tryptophan (acceptor) in position 4. From the relative enhancement of acceptor fluorescence a transfer efficiency of 0.70 +/- 0.04 was determined. The use of this parameter in Förster's equation permitted the calculation of the average intramolecular tyrosine-tryptophan separation, whereby the assumption of random donor-acceptor orientation was made. The resulting average distance of 10.0 +/- 0.3 A suggests some type of a folded conformation and excludes the existence of a fully extended chain in the N-terminal part of the peptide. A comparison with tyrosine-tryptophan distances observed in other biologically active polypeptides is made.

Amino Acid Sequence↗
PubMed1978

Comparative effects of synthetic and natural vasoactive intestinal peptide on pancreatic and biliary secretion and on glucose and insulin blood levels in the dog.

The effects of synetic porcine vasoactive intestinal peptide (VIP) on pancreatic and biliary secretion and on glucose, insulin and calcium blood levels were examined in the dog and compared with the effects of natural porcine VIP. Synthetic VIP was a secretin-like partial agonist of pancreatic and biliary secretion with efficacies relative to secretin of 0.27 and 0.41, respectively. Consistent with its weak secretin-like action, synthetic VIP augmented the pancreatic response to CCK-OP and the submaximal but not the maximal response to secretin. Synthetic VIP also produced a dose-dependent increase in blood glucose levels and a synchronous and proportionate increase in blood insulin levels. A slight increase in total calcium levels was equivocal. The effects of antural VIP on pancreatic and biliary secretion and on glucose and insulin blood levels were identical to those of synthetic VIP. The identity of effects supports the validity of the postulated structure of porcine VIP. Although elicited at high doses, the effects of VIP on exocrine and endocrine secretion may be relevant physiologically in the context of a neurocrine or paracrine role for VIP.

Animals↗