Synthesis of 1-β-Mercaptopropionic Acid Oxytocin (Desamino-oxytocin), a Highly Potent Analogue of Oxytocin

Vigneaud, Vincent du; Winestock, Gershen.; Murti, V. V. S.; Hope, D. B.; Kimbrough, Raymond D.

doi:10.1016/s0021-9258(18)64530-2

Cited by 94 publications

(23 citation statements)

References 9 publications

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“…The decrease in activities resulting from the increase in ring size upon going from 4-glycine-oxytocin to 4-3-alanine-oxytocin recalls the very recent findings in this laboratory (Jarvis and du Vigneaud, 1964) involving structural changes in a highly active analog of oxytocin, deamino-oxytocin (1-3-mercaptopropionic acid-oxytocin) (du Vigneaud et al, 1960;Hope et al, 1962). By replacing the 3-mercaptopropionic acid residue in the 1 position by the homologous -mercaptobutyric acid residue, an analog containing a 21-membered ring, --mercaptobutyric acid-oxytocin, was obtained.…”

Section: Discussionsupporting

confidence: 54%

4-β-Alanine-oxytocin: An Oxytocin Analog Containing a Twenty-one-membered Disulfide Ring^*

Manning¹,

Vigneaud²

1965

Biochemistry

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4-/3-Alanine-oxytocin, an analog of oxytocin containing a /3-alanine residue in place of the glutamine residue in the 4 position in the hormone, has been synthesized and tested for various pharmacological activities in comparison with 4-glycine-oxytocin. Both of these analogs lack the carboxamide-containing side T A he synthesis of oxytocin (du Vigneaud et a/., 1953, 1954), the principal oxytocic and milk-ejecting hormone of the posterior pituitary gland, has provided a means of studying the relationship of chemical structure to biological activity in this octapeptide hormone, the structure of which is shown in Figure 1.Efforts to elucidate this relationship in this and other laboratories during the past decade have centered on the total synthesis of numerous analogs of the hormone, incorporating various modifications of its structure, and the comparison of the pharmacological properties of these synthetic analogs with those of oxytocin. Along with some other aspects of the general problem, the studies in our laboratory have been focused particularly on the importance of the presence of the individual chemical functional groups, the specificity of the 20membered disulfide ring, and the relation of the stereostructure of the seven optically active amino acid residues to the pharmacological manifestations of oxytocin.Recently Drabarek (1964) in this laboratory synthesized three analogs of oxytocin in which the tyrosine, isoleucine, and glutamine residues in positions 2, 3, and 4 were replaced, respectively, by a glycine residue. The only one of these compounds that showed pharmacological activity was 4-glycine-oxytocin, which possessed 5.5 units/mg of oxytocic activity, 17 units/mg of

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Section: Discussionsupporting

confidence: 54%

4-β-Alanine-oxytocin: An Oxytocin Analog Containing a Twenty-one-membered Disulfide Ring^*

Manning¹,

Vigneaud²

1965

Biochemistry

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“…C(4) -0.0493 (4) 0.5835(3) 0.6688 (5) 0.0199(6) 0.0053 (3) 0.0147 (7) 0.0008 (4) -0.0000(7) -0.0030 (4) 0( 1 of magnitude less than experimental error.…”

Section: Description Of the Structurementioning

confidence: 87%

“…This is consistent with the observed C(l)-0(1) and C(l)-0(2) distances which are equal within experimental error. 0.0034(3) 0.0111 (7) -0.0000(3) -0.0009 (5) -0.0003 (3) C(3) -0.1222 (4) 0.4380 (3) 0.6598 (5) 0.0142(5) 0.0074 (4) 0.0148 (7) -0.0012(4) 0.0013 (5) 0.0000(4)…”

Section: Description Of the Structurementioning

confidence: 99%

Crystal and molecular structure of L-azetidine-2-carboxylic acid. A naturally occurring homolog of proline

Berman¹,

McGandy²,

Burgner³

et al. 1969

J. Am. Chem. Soc.

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There is no other hydrogen bonding in the structure. Instead the molecules are held together largely by van der Waal's forces between the methyl and f-butyl parts of the azetidinium ions, and by similar forces between the methyl groups of the methanesulfonate ions.The S-O distances in the methanesulfonate group are 1.438 and 1.439 Á, identical within experimental error. Cesium methanesulfonate38 has two different S-O distances, 1.434 and 1.485 A, but Brandon and Brown38 suggest that an average of these may be as realistic.Since their error must therefore be about ±0.03 A, a more reliable S-O distance is probably given by the present study.The S-C distance of 1.73 A is on the short end of the range reported for S-C bond lengths39 although a bond length of 1.79 Á is reported for the case of dimethyl sulfone.40 The bond lengths and angles in the f-butyl group appear normal.The azetidinium ring geometry is similar to that of azetidinecarboxylic acid:4 the ring is not planar, the bond angles are remarkably close to 90°, and the bond lengths are almost the same.The C-N distances, 1.525 A, are not significantly different from the C-C ring distances of 1.528 A, although these are not so close in azetidinecarboxylic acid. The average ring distance in

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“…Among the many synthetic analogs of oxytocin reported to date only four are known in which a single substitution has brought about a significant enhancement of oxytocic potency relative to that of oxytocin. These substitutions and the resulting highly potent analogs are (1) replacement of the amino group at position 1 by (a) hydrogen, de-amino-oxytocin1-3 or (b) a hydroxy group, [1-(l-2-hydroxy-3-mercaptopropanoic acid)]oxytocin (hydroxyoxytocin);4-6 (2) substitution of threonine for glutamine at position 4, oxytocin;7-8 and (3) replacement of the sulfur atom of the cysteine residue at position 1 with a methylene group, [6-1-cystathionine] oxytocin ([carba-l]oxytocin).9 These modifications also changed the oxytocic-pressor and oxytocic-antidiuretic ratios of the above peptides relative to those of oxytocin. The oxytocic-pressor ratio was enhanced in all peptides with the exception of hydroxy-oxytocin which exhibited a substantially diminished ratio.…”

Section: Synthesis and Some Pharmacological Propertiesmentioning

confidence: 99%

Synthesis and some pharmacological properties of [1-(L-2-hydroxy-3-mercaptopropanoic acid),4-threonine]oxytocin (hydroxy[4-thr]oxytocin), a peptide with strikingly high oxytocic potency, and of [1-(L-2-hydroxy-3-mercaptopropanoic acid)]oxytocin (hydroxy-oxytocin)

Manning¹,

Lowbridge²,

Haldar³

et al. 1976

J. Med. Chem.

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[1-(L-2-Hydroxy-3-mercaptopropanoic acid), 4-threonine]oxytocin (hydroxy[4-Thr]oxytocin) and [1-(l-2-hydroxy-3-mercaptopropanoic acid)]oxytocin (hydroxy-oxytocin) were synthesized by a combination of solid phase and classical methods of peptide synthesis. Protected octapeptides were synthesized by the solid-phase method and 1 + 8 couplings in solution were then employed to furnish the required key protected intermediates. Hydroxy[4-Thr]oxytocin has oxytocic potency as measured in the rat uterus suspended in a Mg2+-free solution, of about 4200 units/mg, eight times the potency of oxytocin, while its antidiuretic potency is approximately equal to that of oxytocin. It thus exhibits a significantly favorable oxytocic-antidiuretic sleectivity. Hydroxy-oxytocin has an oxytocic potency of approximatels 1300 units/mt, 2.5 times that of oxytocin. Threonine substitution in hydroxy-oxytocin has thus caused a significant enhancement in both oxytocic potency and selectivity. The enhancement in oxytocic potency of these two peptides relative to oxytocin and [4-Thr]oxytocin appears to correlate with their lipophilic characteristics, suggesting a significant role of lipophilicity in the interplay of oxytocin-like peptides with oxytocic receptors.

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Synthesis of 1-β-Mercaptopropionic Acid Oxytocin (Desamino-oxytocin), a Highly Potent Analogue of Oxytocin

Cited by 94 publications

References 9 publications

4-β-Alanine-oxytocin: An Oxytocin Analog Containing a Twenty-one-membered Disulfide Ring^*

4-β-Alanine-oxytocin: An Oxytocin Analog Containing a Twenty-one-membered Disulfide Ring^*

Crystal and molecular structure of L-azetidine-2-carboxylic acid. A naturally occurring homolog of proline

Synthesis and some pharmacological properties of [1-(L-2-hydroxy-3-mercaptopropanoic acid),4-threonine]oxytocin (hydroxy[4-thr]oxytocin), a peptide with strikingly high oxytocic potency, and of [1-(L-2-hydroxy-3-mercaptopropanoic acid)]oxytocin (hydroxy-oxytocin)

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Synthesis of 1-β-Mercaptopropionic Acid Oxytocin (Desamino-oxytocin), a Highly Potent Analogue of Oxytocin

Cited by 94 publications

References 9 publications

4-β-Alanine-oxytocin: An Oxytocin Analog Containing a Twenty-one-membered Disulfide Ring*

4-β-Alanine-oxytocin: An Oxytocin Analog Containing a Twenty-one-membered Disulfide Ring*

Crystal and molecular structure of L-azetidine-2-carboxylic acid. A naturally occurring homolog of proline

Synthesis and some pharmacological properties of [1-(L-2-hydroxy-3-mercaptopropanoic acid),4-threonine]oxytocin (hydroxy[4-thr]oxytocin), a peptide with strikingly high oxytocic potency, and of [1-(L-2-hydroxy-3-mercaptopropanoic acid)]oxytocin (hydroxy-oxytocin)

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4-β-Alanine-oxytocin: An Oxytocin Analog Containing a Twenty-one-membered Disulfide Ring^*

4-β-Alanine-oxytocin: An Oxytocin Analog Containing a Twenty-one-membered Disulfide Ring^*