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Biomedical subjects

R Walter

Publications and source records attributed to R Walter.

At least 181 records · Page 10Linked to original sources
PubMed1978

Vasopressin analog with extraordinarily high antidiuretic potency: a study of conformation and activity.

Application of information derived from a three-dimensional model of vasopressin bound to its antidiuretic receptor has resulted in the design and synthesis of a potent analog, [1-deamino, 2-phenylalanine, 7-(3,4-dehydroproline)]-arginine vasopressin; this analog has a specific antidiuretic activity of 13,000 +/- 1,250 units per milligram; noteworthy at these doses is the absence of any detectable pressor activity. Three modifications based on conformational considerations were introduced into the vasopressin molecule in preparing the analog: (i) to enhance binding, a double bond was introduced into the side chain of an amino acid residue occupying a corner position of a beta turn in the vasopressin conformation, (ii) the hydroxyl moiety was deleted from Tyr2, and (iii) to tighten the backbone structure and to enhance the enzymatic resistance of the analog, the NH2-terminal amino group was deleted.

Amino Acid Sequence↗
PubMed1978

ADH and related peptides: effect of pre- or posttraining treatment on puromycin amnesia.

The peptide Z-Pro-Leu-Gly-NH2 attenuated puromycin-induced amnesia in mice when administered 5 days prior to training, while arginine vasopressin, lysine vasopressin and cyclo(Leu-Gly), were effective when given 24 hr before training. The activity of all peptides to inhibit puromycin-induced amnesia decreased as the interval after training and before peptide administration increased, suggesting that the peptides influence memory processes rather than generalized arousal mechanisms.

Animals↗
PubMed1978

A fluorescence study of the binding of calcium and terbium ions to angiotensin.

The interactions of angiotensin II and a synthetic analogue, [Asn1, Val5] angiotensin II, with Ca2+ and Tb3+ have been monitored using the intrinsic fluorescence of the tyrosine residue at position 4 in both molecules. The data indicate that angiotensin II binds both metals with a dissociation constant of approximately 1 X 10(-4) M-1, while no significant binding was observed with the amide analogue. This suggests that the side chain carboxyl group of aspartic acid forms part of the binding site. Since the value of the dissociation constant suggests chelation of the metals by the hormone, the terminal carboxyl group of the peptide is also probably involved in metal binding. The fact that energy transfer was observed between Tb3+ and the tyrosine of angiotensin places the hydroxl or carbonyl group of the tyrosine close to the metal binding site.

Angiotensin II↗
PubMed1978

Solution conformation of peptides by the intramolecular nuclear Overhauser effect experiment. Study of valinomycin-K+.

This study demonstrates how the intramolecular nuclear Overhauser effect (NOE) experiment can be employed quantitatively to select from a set of possible conformations for a peptide or a protein the particular conformation (or a group of conformations) most consistent with the data. This procedure is demonstrated on a model depsipeptide system--valinomycin K+ in CDCl3--for which the solution conformation has been inferred by other methods. The NOE enhancements are very sensitive to the conformations assumed by this antibiotic. It is shown that the set of conformations, collectively labeled as A2 (including the X-ray crystallographic structure) gives a very good description of the NOE enhancements. The structure proposed by Bystrov et al. (1977. Eur. J. Biochem. 78:63) for the uncomplexed valinomycin in nonpolar solvents is also consistent with the experimental data on the potassium complex. Using statistical hypothesis testing involving the Hamilton R-factor ratio criterion, all the other models have been rejected as inconsistent with the experimental data. A general formalism is presented for describing the NOE effects in isotropically reorienting molecules. The formalism is not restricted to the extreme narrowing limit of the rotational correlation times and hence applies to both small and large molecules. Some of the factors that can influence the NOE measurements, viz. anisotropic rotational diffusion, conformational averaging, and nuclear spin diffusion, have been considered in this study.

Magnetic Resonance Spectroscopy↗
PubMed1978

Synthesis and some pharmacological properties (4-beta-(2-thienyl)-L-alanine)oxytocin.

The synthesis and some biological activities of [4-beta-(2-thienyl)-L-alanine]oxytocin are reported. This analogue has been studied in an ongoing exploration of the biological effects of introducing amino acid residues with bulky hydrophobic side chains into the second corner position of the beta turn present in the conformation of the 20-membered ring portion of oxytocin. The analogue was synthesized in stepwise manner by solution techniques utilizing ethylcarbamoyl protection for cysteine side chains. The presence of thienylalanine in position 4 evokes a drastic reduction in both affinity and intrinsic activity; the reduction in intrinsic activity was greater than that found for [Leu4]oxytocin or [Phe4]oxytocin. The analogue possesses 0.51 +/- 0.03 unit/mg of rat uterotonic potency and less than 0.05 unit/mg of rat pressor and rat antidiuretic potency and behaves as a competitive inhibitor of the response to oxytocin in the avian vasodepressor assay with a pA2 value of 7.44 +/- 0.19.

Animals↗
PubMed1978

Replacement of the disulfide bond in oxytocin by an amide group. Synthesis and some biological properties of (cyclo-(1-L-aspartic acid,6-L-alpha,beta-diaminopropionic acid))oxytocin.

As part of a continuing investigation of the steric and electronic functions of the disulfide group in neurohypophyseal hormones on their biological activity, the synthesis of "oxytocin lactam", [cyclo-(1-aspartic acid,6-alpha,beta-diaminopropionic acid)]oxytocin, has been undertaken. The protected nonapeptide was prepared in a stepwise manner by solution techniques; after removal of side-chain protecting groups, formation of the briding amide bonds was accomplished by oxidation-reduction condensation. The analogue possesses rat uterotonic, avian vasodepressor, and rat antidiuretic potencies of 16 +/- 2, 6.6 +/- 0.6, and 5.6 +/- 3.8 units/mg, respectively.

Animals↗
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

Modification of conditioned behavior of rats by neurohypophyseal hormones and analogues.

Vasopressin and other neurohypophyseal peptides affect various processes related to memory and/or learning. A single subcutaneous injection of vasopressin increases resistance to extinction of a pole-jumping avoidance response in rat. This test system has been applied in an attempt to relate structural aspects of neurohypophyseal peptides, analogues, and derivatives with truncated sequences to their effects on conditioned behavior. Thus far it can be concluded that there are more stringent requirements on certain residues in the 20-member covalent ring than in positions 8 and 9 of the linear peptide portion for neurohypophyseal hormones to be active. Critical are the contributions of residues in positions 2, 3, and 5; these results are reminiscent of those from conformation-activity correlations of the endocrine effects of neurohypophyseal hormones, in which the side chain of the residue in position 3 is critical for receptor binding and the side chains of residues in positions 2 and 5 are key for the activation of the receptor. Chemical modifications in position 4 yield analogues that are active and inactive in increasing the resistance to extinction of the avoidance response, depending on the particular structural substitution, similar to results from structure-activity studies of the endocrine activities of neurohypophyseal hormones. Because behavioral activities of vasopressin are more tolerant than endocrine activities to modifications of the hormone in positions 8 and 9, analogues with the most striking dissociation of potencies in learned behavior and endocrine responses are expected to be those with sequence alterations in the linear peptide portion. Peptides with linear part sequences of neurohypophyseal hormones showed little or no activity. The results obtained in this structure-activity study are compared with those of an earlier study in which the ability of various neurohypophyseal peptides to attenuate puromycin-induced amnesia in mice was evaluated.

Animals↗
PubMed1978

Inhibition by Z-Pro-D-Leu of development of tolerance to and physical dependence on morphine in mice.

The peptide-Z-Pro-D-Leu, injected daily in mice receiving morphine chronically, was found to prevent development of physical dependence as measured by changes in body temperature and body weight due either to abrupt or to naloxone-induced withdrawal. On the other hand, administration of Z-Pro-D-Leu only on the last day of morphine treatment did not alter the overt signs of withdrawal. Daily administration of Z-Pro-D-Leu was also effective in blocking the development of tolerance to the analgesic and the hypothermic effects of subsequent challenge doses of morphine. However, the peptide treatment did not alter the acute effects of a challenge dose of morphine on either analgesia or body temperature. No effects on memory were noted, as evaluated in a one-trial passive avoidance task. Clinical implications of the use of Z-Pro-D-Leu are discussed.

Animals↗
PubMed1978

Treatment of central diabetes insipidus in adults and children with desmopressin.

Modification of the natural vasopressin molecule to form desmopressin acetate (DDAVP) resulted in a compound with prolonged antidiuretic activity and virtual elimination of vasopressor activity. Twenty-one patients with central diabetes insipidus who ranged in age from 3 to 68 years were treated with DDAVP, which was administered intranasally in a dosage ranging from 10 microgram every 12 hours to 20 microgram every eight hours. Effective control of symptoms was obtained in all cases. There were no consequential toxic effects. As previously reported, DDAVP appears to be the preferred drug for the management of central diabetes insipidus. Biochemical alteration of hormones may enhance desired therapeutic activity and eliminate toxic effects. The development of DDAVP is an example of the potential for development of useful therapeutic peptides.

Adolescent↗
PubMed1977

Post-proline dipeptidyl aminopeptidase (dipeptidyl aminopeptidase IV) from lamb kidney. Purification and some enzymatic properties.

Post-proline dipeptidyl aminopeptidase (dipeptidylpeptide hydrolase, EC 3.4.14.1), also known as glycylprolyl beta-naphthylamidase or dipeptidyl aminopeptidase IV, was isolated and purified in an overall yield of 20% from autolyzed extracts of lamb kidney by CM-cellulose and column chromatography on DEAE-Sephadex and Sephadex G-200. Purified enzyme was homogeneous by disc gel electrophoresis and ultracentrifugal analysis and was most active at pH 7.8 using Gly-Pro beta-napthylamide as substrate. The Km values for Gly-Pro beta-naphthylamide and Ala-Ala beta-naphthylamide were 0.63 and 0.77 mM, respectively. The proline-containing peptides were hydrolysed more than 10-fold faster. By isoelectric focusing a pI of 4.9 was determined. The enzyme was estimated to be 230 000 +/- 15 000 by the sedimentation equilibrium method and sodium dodecyl sulfate polyacrylamide gel electrophoresis indicating that the enzyme is composed of two identical subunits with molecular weights of 115 000. It was inhibited by the active-site directed, irreversible inhibitor diisopropylphosphorofluorofluoridate. Post-proline dipeptidyl aminopeptidase, in contrast to the endopeptidase post-proline cleaving enzyme [9,10] (Walter R. (1976) Biochim. Biophys. Acta 422, 138-158, and Koida, M. and Walter, R. (1976) J. Biol. Chem. 251, 7593-7599) exhibits no endopeptidase activity. Instead it is an exopeptidase with a high specificity for NH2-terminal-free peptides containing a proline residue in the penultimate position and releases the dipeptide with proline being the COOH-terminal moiety. The name "post-proline dipeptidyl aminopeptidase" is suggested.

Animals↗
PubMed1977

Dose-response relationships in attenuation of puromycin-induced amnesia by neurohypophyseal peptides.

Intracerebral injections of puromycin one day after training of mice in a Y-maze cause amnesia when the animals are tested 7 days later. This amnesia was shown to be attenuated by various neurohypophyseal hormones, analogs and fragments, administered subcutaneously immediately after training. Dose-response relationships have been obtained for the attenuation of puromycin-induced amnesia in mice by selected neurohypophyseal peptides. All of the compounds tested reduce the amnesia in a dose-related way, suggesting that these peptides may interact with specific receptors to induce their central effect. Among the peptides studied the two most potent--i.e., those that cause substantial retention of memory at the lowest doses--are the neurohypophyseal hormone arginine vasopressin and Z-prolyl-leucyl-glycinamide (Z-MIF).

Amnesia↗