Bicyclization of a Weak Oxytocin Agonist Produces a Highly Potent Oxytocin Antagonist

Patricia S. Hill; D. David Smith; Victor J. Hruby; Patricia S. Hill; Jirina Slaninova

doi:10.1021/ja00164a035

Bicyclization of a Weak Oxytocin Agonist Produces a Highly Potent Oxytocin Antagonist

Patricia S. Hill, D. David Smith, Victor J. Hruby, Patricia S. Hill, Jirina Slaninova

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Abstract

[Mpa¹, Glu⁴, Cys⁶, Lys⁸]oxytocin was prepared and found to be a very weak agonist in the oxytocic assay with about 1/1400 the potency of the native hormone. Bicyclization of this compound via a lactam bridge between the Glu⁴ δ-carboxyl group and the ϵ-amino group of Lys⁸ led to the bicyclic analogue 4,8-cyclo[Mpa¹, Glu⁴, Cys⁶, Lys⁸]oxytocin. This bicyclic peptide acts as a very potent antagonist of oxytocin in the rat uterus assay with an in vitro pA₂ value of 8.2. In the in vivo oxytocic assay the pA₂ value was 6.45. The peptide displays mixed agonist/antagonist character in the in vivo galactogogic assay. The implications of these results to hormone agonist and antagonist activity are discussed with respect to earlier studies on constrained oxytocin antagonists and the results from the X-ray crystal structure of deaminooxytocin.

Original language	English (US)
Pages (from-to)	3110-3113
Number of pages	4
Journal	Journal of the American Chemical Society
Volume	112
Issue number	8
DOIs	https://doi.org/10.1021/ja00164a035
State	Published - Jan 1990
Externally published	Yes

All Science Journal Classification (ASJC) codes

Catalysis
Chemistry(all)
Biochemistry
Colloid and Surface Chemistry

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title = "Bicyclization of a Weak Oxytocin Agonist Produces a Highly Potent Oxytocin Antagonist",

abstract = "[Mpa1, Glu4, Cys6, Lys8]oxytocin was prepared and found to be a very weak agonist in the oxytocic assay with about 1/1400 the potency of the native hormone. Bicyclization of this compound via a lactam bridge between the Glu4 δ-carboxyl group and the ϵ-amino group of Lys8 led to the bicyclic analogue 4,8-cyclo[Mpa1, Glu4, Cys6, Lys8]oxytocin. This bicyclic peptide acts as a very potent antagonist of oxytocin in the rat uterus assay with an in vitro pA2 value of 8.2. In the in vivo oxytocic assay the pA2 value was 6.45. The peptide displays mixed agonist/antagonist character in the in vivo galactogogic assay. The implications of these results to hormone agonist and antagonist activity are discussed with respect to earlier studies on constrained oxytocin antagonists and the results from the X-ray crystal structure of deaminooxytocin.",

author = "Hill, {Patricia S.} and {David Smith}, D. and Hruby, {Victor J.} and Hill, {Patricia S.} and Jirina Slaninova",

year = "1990",

month = jan,

doi = "10.1021/ja00164a035",

language = "English (US)",

volume = "112",

pages = "3110--3113",

journal = "Journal of the American Chemical Society",

issn = "0002-7863",

publisher = "American Chemical Society",

number = "8",

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T1 - Bicyclization of a Weak Oxytocin Agonist Produces a Highly Potent Oxytocin Antagonist

AU - Hill, Patricia S.

AU - David Smith, D.

AU - Hruby, Victor J.

AU - Hill, Patricia S.

AU - Slaninova, Jirina

PY - 1990/1

Y1 - 1990/1

N2 - [Mpa1, Glu4, Cys6, Lys8]oxytocin was prepared and found to be a very weak agonist in the oxytocic assay with about 1/1400 the potency of the native hormone. Bicyclization of this compound via a lactam bridge between the Glu4 δ-carboxyl group and the ϵ-amino group of Lys8 led to the bicyclic analogue 4,8-cyclo[Mpa1, Glu4, Cys6, Lys8]oxytocin. This bicyclic peptide acts as a very potent antagonist of oxytocin in the rat uterus assay with an in vitro pA2 value of 8.2. In the in vivo oxytocic assay the pA2 value was 6.45. The peptide displays mixed agonist/antagonist character in the in vivo galactogogic assay. The implications of these results to hormone agonist and antagonist activity are discussed with respect to earlier studies on constrained oxytocin antagonists and the results from the X-ray crystal structure of deaminooxytocin.

AB - [Mpa1, Glu4, Cys6, Lys8]oxytocin was prepared and found to be a very weak agonist in the oxytocic assay with about 1/1400 the potency of the native hormone. Bicyclization of this compound via a lactam bridge between the Glu4 δ-carboxyl group and the ϵ-amino group of Lys8 led to the bicyclic analogue 4,8-cyclo[Mpa1, Glu4, Cys6, Lys8]oxytocin. This bicyclic peptide acts as a very potent antagonist of oxytocin in the rat uterus assay with an in vitro pA2 value of 8.2. In the in vivo oxytocic assay the pA2 value was 6.45. The peptide displays mixed agonist/antagonist character in the in vivo galactogogic assay. The implications of these results to hormone agonist and antagonist activity are discussed with respect to earlier studies on constrained oxytocin antagonists and the results from the X-ray crystal structure of deaminooxytocin.

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DO - 10.1021/ja00164a035

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JO - Journal of the American Chemical Society

JF - Journal of the American Chemical Society

SN - 0002-7863

IS - 8

ER -

Bicyclization of a Weak Oxytocin Agonist Produces a Highly Potent Oxytocin Antagonist

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