Synthesis and Biological Activity of a New Potent Analogue of Oxytocin

Berde, B.; Ra, Boissonnas; Guttmann, St.; Pa, Jaquenoud; Konzett, H; Jp, Waller

doi:10.1038/178260a0

Cited by 26 publications

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“…In the first three of these tests, the effectiveness of the unknown preparation was estimated by bracketing doses of the unknown with doses of the standard. In the diuresis experiments on salineloaded rats, synthetic oxytocin, also A NEW ANALOGUE OF OXYTOCIN13 known as Syntocinon (Boissonnas et al, 1955 ;Konzett, Berde, and Cerletti, 1956), was used for this purpose.…”

Section: Methodsmentioning

confidence: 99%

“…Recent work in this laboratory (Boissonnas et al, 1956a;Berde et al, 1957;Berde and Cerletti, 1957;Guttmann et al, 1957;Berde and Cerletti, 1958) and elsewhere (Katsoyannis, 1957;Ressler and du Vigneaud, 1957;Ressler and Rachele, 1958) on the biological activity of synthetic analogues of oxytocin has revealed that relatively small chemical changes in the oxytocin molecule may lead to a decrease, increase, or modification of its characteristic effects.…”

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“…However, replacing the isoleucyl group of the oxytocin molecule by a valyl group (valyl3-oxytocin) brings a striking increase of the in vivo activity on the uterus and on the mammary gland, together with a decrease of the pressor and antidiuretic potency (Boissonnas et al, 1956a;Berde et al, 1957). This means that the uterusstimulating and milk-ejecting effects of valyJ3-oxytocin are even more specific than those of the natural oxytocic hormone.…”

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confidence: 99%

“…Such an analogue of oxytocin with 'a phenylalanyl group substituted for the tyrosyl group, phenylalanyl2-oxytocin (Table I), has recently been synthesized in our Department of Pharmaceutical Chemistry by P. A. Jaquenoud in 1958 using the same method of synthesis as previously used for the synthesis of oxytocin (Boissonnas, Guttmann, Jaquenoud, and Waller, 1955): To obtain the cyclic octapeptide, 20 mg. of the corresponding nonapeptide (Boissonnas, Guttmann, Jaquenoud, and Waller, 1956b) was dissolved in 5 ml. of liquid ammonia, and reduced with sodium (du Vigneaud, Ressler, Swan, Roberts, and Katsoyannis, 1954).…”

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confidence: 99%

“…The analogue dealt with in this paper would therefore be named phenylalanyl2-oxytocin. The oxytocin analogues which have so far been investigated (Rudinger, Honzl, and Zaoral, 1956;Boissonnas, Guttmann, Jaquenoud, Waller, Konzett, and Berde, 1956a;Berde, Doepfner, and Konzett, 1957;Katsoyannis, 1957;Ressler and du Vigneaud, 1957;Ressler and Rachele, 1958) would then be specified as follows: phenylalanyl3-oxytocin (this is also known as oxypressin or the P-analogue); leucyJ3-oxytocin (also known as the L-analogue); valyl3-oxytocin (also known as valyl-oxytocin or the V-analogue); glutaminyl5-oxytocin (also known as the G-analogue); and isoglutaminyl4-oxytocin (also known as isoglutamine isomer of oxytocin or isoglutamine-oxytocin). With this nomenclature, the vasopressins could also be described as oxytocin analogues, namely argininevasopressin as phenylalanyl3-arginyl8-oxytocin and lysine-vasopressin as phenylalanyl3-lysyl8-oxytocin.…”

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The Biological Activity of a New Analogue of Oxytocin in Which the Tyrosyl Group Is Replaced by Phenylalanyl

Konzett¹,

Berde²

1959

British Journal of Pharmacology and Chemotherapy

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A new synthetic analogue of oxytocin with a phenylalanyl group instead of a tyrosyl group has been investigated. The most prominent biological properties of this peptide were its oxytocic activity on the rat or cat uterus in vivo and on milk-ejection pressure in the rabbit. Another remarkable feature was the striking difference in pressor activity measured in spinal cats and in anaesthetized rats. The presence of the phenylalanyl group in the molecule in the above-mentioned position did not increase the antidiuretic potency in unanaesthetized rats. The authors propose a nomenclature for the peptides related to oxytocin and vasopressin.As chemical and biological work on peptides related to oxytocin and vasopressin progresses, the need for a simple and clear nomenclature in this field becomes increasingly greater. We should therefore like to propose a nomenclature along the lines of that already in use for polypeptides of the hypertensin type (see, for example, Rittel, Iselin, Kappeler, Riniker, and Schwyzer, 1957). The amino-acid groups in the oxytocin molecule would be numbered as follows:

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The Biological Activity of a New Analogue of Oxytocin in Which the Tyrosyl Group Is Replaced by Phenylalanyl

Konzett¹,

Berde²

1959

British Journal of Pharmacology and Chemotherapy

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Synthèse de la Phé²‐oxytocine

Jaquenoud

Boissonnas

1959

Helvetica Chimica Acta

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Rac. 2-dehydro-emetine (XV) and rac. 2-dehydro-isoemetine (XVI) have been synthcsizcd in fivc steps and in good yicld from 2-oxo-3-ethyl-9,10-dimethoxy-l, 2,3, 4,6, . Homologues and analogues of XV and XVI with other substituents have been obtained in the same way.Rac. 2-dchydro-emetine (XV) and its analogucs with other substituents in the isoquinoliiie part exhibit high activity in infections caused by Entanaoeba histolytica. The compounds substitutcd in %position with groups other than an ethyl and all dcrivatives of the clehydro-isometine series show little or no activity. Chemischc Forschungsabtcilung dcr F. HOFFMAXX-LA ROCHE & Co. AG., Basel 86. Synthkse de la PhC2-oxytocine l ) par P.-A. Jaquenoud ct R. A. Boissonnas (12 I11 59)Nous avons dCcrit dans des travaux prCcCdents la synthkse z, 3, 4, et les propriCtCs biologiques4) 5, de diffCrents analogues de l'oxytocine, dans lesquels ou bien l'isoleucine en position 3 Ctait rcmplacCe par la leucine, la valine ou la phknylalanine, ou bien l'asparagine en position 5 par la glutamine.Dam lc prCsent travail, nous rapportons la synthhse d'un autre analogue de l'oxytocine, dans lequel l a tyrosine, en position 2, a CtC remplacCe par la phknylalanine. Cette PhC2-oxytocine (VII) ne posskde donc pas l'hydroxyle phholique present dans l'oxytocine. L'Ctude biologique de cet analogue doit permettre de faire ressortir l'influence de cette fonction hydroxylique sur les diffdrentes activitCs biologiques caractkristiques de l'osytocine.Le schema de synthkse que nous avons utilisC est bask sur le principe que nous avons suivi dans nos travaux prCc6dents2) 3, 6, (voir schCma de synthcse) 7). l) Nous adoptons pour la designation des analogues dc l'oxytocine la nomenclature cEjk utilis6e pr6c6demment dans ce journal pour les analogues dc I'hypertensine par K. SCHWYZER e t coll. (Helv. 40, 614 (1957) ; 41, 1273, 1287 (1958), nomenclature dans laquelle le corps de base e i t pr$c6d6 du I~O T T~ d c l'acide amin6 introduit i la place d'un acide amind d u corps de base avec, en indice, la position, c o m p t k depuis I'extrCmitC N-terminale de la chaine, oh a eu lieu la substitution.

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Synthèse de dix analogues de l'oxytocine et de la lysine‐vasopressine, contenant de la sérine, de l'histidine ou du tryptophane en position 2 ou 3

Guttmann

Boissonnas

1960

Helvetica Chimica Acta

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200HELVETICA CHIMICA ACTA par contre-courant comme pour la Tyr3-oxytocine (XVIII) ci-dessus. On obtient un sommet principal de K = 0,43 et un sommet secondaire de K = 0,16. Le contenu des tubes centraux du sommet principal est reuni et &vapor6 au vide. Le produit obtenu represente environ la moitit: de l'azote peptidique de depart et est homogene L la chromatographie (RfM = 0,69; RfA = 0,55; Rf, = 0,39) et L l'dlectrophorkse (El,9 = 0,58 Try; E5,8 = 0,42 His), aprks rCvClation par la ninhydrine, le bleu de bromoph6no1, le FOLIN et le chlore-iodure-amidon.ActivitBs biologiq~esl~), exprimkes en unites internationales par mg : baisse de la pression sanguine du coq, moins de 0,01; prcssion sanguine du rat, moins de 0,01; inhibition de la diurkse du rat, env. 0,001 ; contraction de l'utCrus is016 de rat, moins de 0,01. SUMMARYThe following analogues of oxytocin and lysine-vasopressin have been synthesized : Tyr3-oxytocin, Phe2-Phe3-oxytocin, Phe2-Tyr3-oxytocin, Phe2-Lyss-vasopressin, Tyr3-Lyss-vasopressin, Phe2-Tyr3-Lyss-vasopressin.The method of synthesis is based on the condensation of the azides of tripeptides, formed by coupling N-CBO-S-benzyl-L-cysteinyl-L-tyrosine or N-CBO-S-benzyl-Lcysteinyl-L-phenylalanine with L-phenylalanine methylester or L-tyrosine methylester, with ~-glutaminyl-~-asparaginyl-S-benzyl-~-cysteinyl-~-prolyl-~-leucyl-glycinamide or ~-glutaminyl-~-asparaginyl-S-benzyl-~-cysteinyl-~-prolyl-E-N-tosyl-~-lysylglycinamide. Cleavage of the protecting groups of the resulting nonapeptides with sodium in liquid ammonia, oxidation with air in diluted aqueous solution and purification by counter-current distribution, affords the desired cyclic nonapeptide amides.The relations between the constitutions and the biological activities of these new analogues are discussed. . lo) Seuls les divers hydrazides ont montre une tache secondaire, dont la proportion croit avec le temps de sejour dans le melange de scission, e t qui est probablement due ? I un produit de reaction secondaire entre le bromure de benzyle forme e t la fonction hydrazide. 17) Voir la partie experimentale.

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Synthesis and Biological Activity of a New Potent Analogue of Oxytocin

Cited by 26 publications

References 2 publications

The Biological Activity of a New Analogue of Oxytocin in Which the Tyrosyl Group Is Replaced by Phenylalanyl

The Biological Activity of a New Analogue of Oxytocin in Which the Tyrosyl Group Is Replaced by Phenylalanyl

Synthèse de la Phé²‐oxytocine

Synthèse de dix analogues de l'oxytocine et de la lysine‐vasopressine, contenant de la sérine, de l'histidine ou du tryptophane en position 2 ou 3

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Synthesis and Biological Activity of a New Potent Analogue of Oxytocin

Cited by 26 publications

References 2 publications

The Biological Activity of a New Analogue of Oxytocin in Which the Tyrosyl Group Is Replaced by Phenylalanyl

The Biological Activity of a New Analogue of Oxytocin in Which the Tyrosyl Group Is Replaced by Phenylalanyl

Synthèse de la Phé2‐oxytocine

Synthèse de dix analogues de l'oxytocine et de la lysine‐vasopressine, contenant de la sérine, de l'histidine ou du tryptophane en position 2 ou 3

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Synthèse de la Phé²‐oxytocine