Effects of conformational constraint in 2- and 8-cycloleucine analogues of oxytocin and [1-penicillamine] oxytocin examined by circular dichroism and biosassay

Ivo Fric, Jan Hlavacek, Todd W. Rockway, W. Y. Chan, Victor J Hruby

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

The analogues of oxytocin and [1-penicillamine]oxytocin, containing a cycloleucine (Cle) residue in position 2 or 8, were investigated by means of circular dichroism measurements in different solvents, and the results examined in terms of their biological activities. A cycloleucine residue in position 2 substantially reduces the free conformational space of the hormone 20-membered ring moiety (including the disulfide group), and stabilizes a conformation which is close to one of the possible conformations of oxytocin and involves a β-turn. In position 8, the Cle residue affects the conformation of the Tyr2 side chain, apparently forcing it away from the space above the 20-membered disulfide ring. However, it does not appear that the Cle residue has any significant effect on the overall backbone conformation of the hormone. The steric effect of the penicillamine residue in position 1 on the conformation of the disulfide group and Tyr2 side chain from previous investigations is further confirmed. The synthesis and biological potency of [1-penicillamine, 8-cycloleucine]oxytocin is described. This analogue exhibits a strong inhibitory effect on the uterotonic activity of oxytocin in vitro. It also inhibited the vasopressor response to vasopressin.

Original languageEnglish (US)
Pages (from-to)9-15
Number of pages7
JournalJournal of Protein Chemistry
Volume9
Issue number1
DOIs
StatePublished - Feb 1990

Fingerprint

Cycloleucine
Dichroism
Oxytocin
Circular Dichroism
Conformations
Disulfides
Penicillamine
Hormones
Bioactivity
Vasopressins
penicillamine(1)-oxytocin

Keywords

  • analogues
  • circular dichioism
  • conformation
  • conformational constraint
  • Oxytocin
  • oxytocin antagonist

ASJC Scopus subject areas

  • Biochemistry

Cite this

Effects of conformational constraint in 2- and 8-cycloleucine analogues of oxytocin and [1-penicillamine] oxytocin examined by circular dichroism and biosassay. / Fric, Ivo; Hlavacek, Jan; Rockway, Todd W.; Chan, W. Y.; Hruby, Victor J.

In: Journal of Protein Chemistry, Vol. 9, No. 1, 02.1990, p. 9-15.

Research output: Contribution to journalArticle

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abstract = "The analogues of oxytocin and [1-penicillamine]oxytocin, containing a cycloleucine (Cle) residue in position 2 or 8, were investigated by means of circular dichroism measurements in different solvents, and the results examined in terms of their biological activities. A cycloleucine residue in position 2 substantially reduces the free conformational space of the hormone 20-membered ring moiety (including the disulfide group), and stabilizes a conformation which is close to one of the possible conformations of oxytocin and involves a β-turn. In position 8, the Cle residue affects the conformation of the Tyr2 side chain, apparently forcing it away from the space above the 20-membered disulfide ring. However, it does not appear that the Cle residue has any significant effect on the overall backbone conformation of the hormone. The steric effect of the penicillamine residue in position 1 on the conformation of the disulfide group and Tyr2 side chain from previous investigations is further confirmed. The synthesis and biological potency of [1-penicillamine, 8-cycloleucine]oxytocin is described. This analogue exhibits a strong inhibitory effect on the uterotonic activity of oxytocin in vitro. It also inhibited the vasopressor response to vasopressin.",
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