[5-Aspartic acid]-oxytocin: first 5-position neurohypophyseal hormone analog possessing significant biological activity

Walter, Roderich; Skala, Gerald; Smith, Clark W.

doi:10.1021/ja00471a053

Cited by 14 publications

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“…In the proposed conformational model of oxytocin, based on NMR studies, this H-bond is assumed to stabilize a β-turn, involving the Tyr-Ile-Gln-Asn sequence. This β-turn structure has been suggested to be one of building elements in overall conformation necessary for recognition by corresponding receptors and transduction of biological activities, as well [9][10][11][12][22][23][24][25] . By introducing the methyleneoxy surrogate, formation of this hydrogen bond was avoided and the flexible twenty-membered disulfide ring could not adopt a proper conformation for the interaction with the receptor.…”

Section: Resultsmentioning

confidence: 99%

“…We have been interested in CH 2 O and CH 2 S surrogates for several years 2-6 since they offer polar and flexible structures resistant to proteolytic envasopressin 11 due to its side-chain interaction with the receptor binding site (even though some findings 12,13 proposed a more extensive exploration of structure-function relations at this residue because of the potency found in Asp 5 containing analogues). Also the Tyr 2 residue was postulated to exhibit an essential function in the interaction of both the hormones with corresponding receptors and the side-chain of this residue was designed to play an important role in the bioactive conformation [14][15][16] .…”

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confidence: 99%

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Synthesis, Bioassay and NMR Study of Methyleneoxy Isosters of Oxytocin and Vasopressin

Mařı́k

Budêšínský

Slaninová

et al. 2002

Collect. Czech. Chem. Commun.

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Syntheses of pseudodipeptides H-Tyrψ[CH 2 O]Ile-OH and H-Tyrψ[CH 2 O]Phe-OH were carried out using the intramolecular Williamson reaction of O-benzyltyrosinol with ethyl chloroacetate followed by N-protection and aldol reaction of the corresponding morpholin-3-one in position C 2 with butanone or benzaldehyde, elimination of the hydroxy group to give derivatives with a double bond either as the E/Z (1 : 1) diastereomeric mixture in the case of the former derivative or as the Z-isomer only in the case of the latter one. Stereoselective hydrogenation and hydrolysis of both the lactams yielded the corresponding pseudodipeptides lacking the carbonyl group as a hydrogen bond donor. The introduction of the pseudodipeptides into positions 2 and 3 of oxytocin and vasopressin caused total absence of all biological activities in the formed analogues. The results of the bioassay and NMR study confirmed the importance of the H-bond between the backbone carbonyl of the Tyr 2 and NH proton of the Asn 5 residues for stabilization of the β-turn in the cyclic hexapeptide part of both the hormones and for their biological activity.Isosteric bond introduction into peptides is motivated by the limited usage of peptides as potential therapeutic agents because of their fast enzymatic degradation and a poor transport through biomembranes. The replacement of a peptide bond with a suitable isostere (surrogate) can increase the stability of a peptide toward enzymatic degradation, prolong the half-time of peptide action and improve peptides transport into a cell 1 . On the other hand, the substitution with surrogate of larger flexibility or rigidity can influence noncovalent interactions in a given peptide molecule and, consequently, its space structure and interaction with a corresponding receptor and finally lead to a changed biological potency.We have been interested in CH 2 O and CH 2 S surrogates for several years 2-6 since they offer polar and flexible structures resistant to proteolytic en-

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

Synthesis, Bioassay and NMR Study of Methyleneoxy Isosters of Oxytocin and Vasopressin

Mařı́k

Budêšínský

Slaninová

et al. 2002

Collect. Czech. Chem. Commun.

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“…Gln 4 is non-significant in the uterotonic activity of OT (Manning, Coy, & Sawyer, 1970). Asn 5 is known to be the most vital for OT activity (Walter, Skala, & Smith, 1978). The significant influences on binding to OT receptor may also be due to the modifications at position 1 (Cys 1 ) (Tarnowska et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

Conformations of a model cyclic hexapeptide, CYIQNC:¹H-NMR and molecular dynamics studies

Kulkarni

Ojha

2014

Journal of Biomolecular Structure and Dynamics

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Solution conformation of the cyclic hexapeptide sequence, [cyclo-S-Cys-Tyr-Ile-Gln-Asn-Cys-S] (CYIQNC) - a disulfide-linked fragment of a neurohypophyseal peptide hormone oxytocin (OT) - has been investigated by high-field one-dimensional (1D) and two-dimensional (2D) NMR spectroscopic methods and compared with the results obtained from computer simulation studies. (1)H-NMR results based on temperature dependence of amide proton chemical shifts and nuclear Overhauser effect indicate that peptide in solution populates different conformations, characterized by two fused β-turns. The segment Ile(3)-Gln(4)-Asn(5)-Cys(6) yields a preferred type-III β-turn at residues 4, 5 (HB, 3HN → 6CO), while the segment Cys(6), Cys(1)-Tyr(2)-Ile(3) exhibits inherently weaker, flexible β-turn either of type I/II'/III/half-turn at residues 1, 2 (HB, 6HN → 3CO). The computer simulation studies using a mixed protocol of distance geometry-simulated annealing followed by constrained minimization, restrained molecular dynamics, and energy minimization showed the possibility of existence of additional conformations with the hydrogen bonds, (a) 5HN → 3CO and (b) 2HN → 6CO. These results, therefore, indicate that the additional conformations obtained from both NMR and simulation studies can also be possible to the peptide. These additional conformations might have very small population in the solution and did not show their signatures in these conditions. These findings will be helpful in designing more analogs with modifications in the cyclic moiety of OT.

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“…Removal or substitution of the amide group of Asn led to analogues with very diminished activity. The most active analogue was [Asp 5 ]OT, which retained 4% uterotonic activity of OT (Walter et al, 1978). Most modifications of the glycine amide in position 9 led to a considerably reduced uterotonic activity, with the exception of the 9-aminoacetonitrile analogue which was even more active than the parent hormone (Roy et al, 1983).…”

Section: Introductionmentioning

confidence: 99%

Oxytocin analogues with amide groups substituted by tetrazole groups in position 4, 5 or 9.

Manturewicz

Grzonka²,

Borovičková³

et al. 2007

Acta Biochim Pol

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Eleven oxytocin analogues substituted in position 4, 5 or 9 by tetrazole analogues of amino acids were prepared using solid-phase peptide synthesis method and tested for rat uterotonic in vitro and pressor activities, as well as for their affinity to human oxytocin receptor. The tetrazolic group has been used as a bioisosteric substitution of carboxylic, ester or amide groups in structure-activity relationship studies of biologically active compounds. Replacement of the amide groups of Gln(4) and Asn(5) in oxytocin by tetrazole analogues of aspartic, glutamic and alpha-aminoadipic acids containing the tetrazole moiety in the side chains leads to analogues with decreased biological activities. Oxytocin analogues in which the glycine amide residue in position 9 was substituted by tetrazole analogues of glycine had diminished activities as well. The analysis of differences in rat uterotonic activity and in the affinity to human oxytocin receptors of analogues containing either an acidic 5-substituted tetrazolic group or a neutral 1,5- or 2,5-tetrazole nucleus makes it possible to draw some new conclusions concerning the role of the amide group of amino acids in positions 4, 5 and 9 of oxytocin for its activity. The data suggest that the interaction of the side chain of Gln(4) with the oxytocin receptor is influenced mainly by electronic effects and the hydrogen bonding capacity of the amide group. Steric effects of the side chain are minor. Substitution of Asn(5) by its tetrazole derivative gave an analogue of very low activity. The result suggests that in the interaction between the amide group of Asn(5) and the binding sites of oxytocic receptor hydrogen bonds are of less importance than the spatial requirements for this group.

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[5-Aspartic acid]-oxytocin: first 5-position neurohypophyseal hormone analog possessing significant biological activity

Abstract: Grant No. GM-17574. We also wish to express our appreciation to Dr. Norman Sutin for helpful conversations and for allowing us the use of the facilities at Brookhaven National Laboratory for several experiments.

Cited by 14 publications

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Synthesis, Bioassay and NMR Study of Methyleneoxy Isosters of Oxytocin and Vasopressin

Synthesis, Bioassay and NMR Study of Methyleneoxy Isosters of Oxytocin and Vasopressin

Conformations of a model cyclic hexapeptide, CYIQNC:¹H-NMR and molecular dynamics studies

Oxytocin analogues with amide groups substituted by tetrazole groups in position 4, 5 or 9.

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[5-Aspartic acid]-oxytocin: first 5-position neurohypophyseal hormone analog possessing significant biological activity

Abstract: Grant No. GM-17574. We also wish to express our appreciation to Dr. Norman Sutin for helpful conversations and for allowing us the use of the facilities at Brookhaven National Laboratory for several experiments.

Cited by 14 publications

References 0 publications

Synthesis, Bioassay and NMR Study of Methyleneoxy Isosters of Oxytocin and Vasopressin

Synthesis, Bioassay and NMR Study of Methyleneoxy Isosters of Oxytocin and Vasopressin

Conformations of a model cyclic hexapeptide, CYIQNC:1H-NMR and molecular dynamics studies

Oxytocin analogues with amide groups substituted by tetrazole groups in position 4, 5 or 9.

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Conformations of a model cyclic hexapeptide, CYIQNC:¹H-NMR and molecular dynamics studies