Structure-activity studies of a novel bicyclic oxytocin antagonist

D. David Smith, Jirina Slaninova, Victor J Hruby

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Abstract

In this report, we describe structure-activity studies of the bicyclic oxytocin antagonist [Mpa1,cyclo(Glu4,Lys8)oxytocin. The monocylic analogue [dPen1,Glu4,Lys8)]oxytocin was a weak oxytocin antagonist with a pA2 value of 5.8 in the uterotonic assay. Bicyclization of this analogue yielded [dPen1,cyclo(Glu4,Lys8)]oxytocin, a potent antagonist of oxytocin in the uterotonic assay (pA2 8.74) with a potency 3 times greater than that of [Mpa1,cyclo(Glu4,Lys8)]oxytocin. [dPen1,cyclo(Glu4,Lys8]oxytocin also was a weak antagonist in the pressor assay with a pA2 of 6.3. To establish if the potent antagonistic effects of these bicyclic compounds was because of the lactam ring or merely the result of obtaining an optimal degree of lipophilicity of the side chains in positions 4 and 8, we synthesized a series of analogues containing neutral and/or charged groups on these side chains. Monocyclic derivatives of [Mpa1,Gln4,Lys(CHO)8]oxytocin were moderate to weak agonists of oxytocin all following classical structure-activity profiles of oxytocin. The monocyclic derivatives of [dPen1,Gln4,Lys(CHO)8]oxytocin were antagonists of oxytocin which was attributed to the dPen1 substitution. However, the potency of all of these latter derivatives was at least 1 order of magnitude less than [dPen1,cyclo(Glu4,Lys8)]oxytocin. These results suggest that the potent antagonistic properties of the bicyclic analogues [Mpa1,cyclo(Glu4,Lys8)]oxytocin and [dPen1,cyclo(Glu4,Lys8)]oxytocin can be attributed to the effect of the lactam bridge on the conformational flexibility and topographical properties of the analogues, rendering them more favorable for binding to the receptor in such a manner as to prevent transduction of a biological response.

Original languageEnglish (US)
Pages (from-to)1558-1563
Number of pages6
JournalJournal of Medicinal Chemistry
Volume35
Issue number9
StatePublished - 1992

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Oxytocin
Lactams
Assays
Derivatives

ASJC Scopus subject areas

  • Organic Chemistry

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Structure-activity studies of a novel bicyclic oxytocin antagonist. / Smith, D. David; Slaninova, Jirina; Hruby, Victor J.

In: Journal of Medicinal Chemistry, Vol. 35, No. 9, 1992, p. 1558-1563.

Research output: Contribution to journalArticle

Smith, D. David ; Slaninova, Jirina ; Hruby, Victor J. / Structure-activity studies of a novel bicyclic oxytocin antagonist. In: Journal of Medicinal Chemistry. 1992 ; Vol. 35, No. 9. pp. 1558-1563.
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abstract = "In this report, we describe structure-activity studies of the bicyclic oxytocin antagonist [Mpa1,cyclo(Glu4,Lys8)oxytocin. The monocylic analogue [dPen1,Glu4,Lys8)]oxytocin was a weak oxytocin antagonist with a pA2 value of 5.8 in the uterotonic assay. Bicyclization of this analogue yielded [dPen1,cyclo(Glu4,Lys8)]oxytocin, a potent antagonist of oxytocin in the uterotonic assay (pA2 8.74) with a potency 3 times greater than that of [Mpa1,cyclo(Glu4,Lys8)]oxytocin. [dPen1,cyclo(Glu4,Lys8]oxytocin also was a weak antagonist in the pressor assay with a pA2 of 6.3. To establish if the potent antagonistic effects of these bicyclic compounds was because of the lactam ring or merely the result of obtaining an optimal degree of lipophilicity of the side chains in positions 4 and 8, we synthesized a series of analogues containing neutral and/or charged groups on these side chains. Monocyclic derivatives of [Mpa1,Gln4,Lys(CHO)8]oxytocin were moderate to weak agonists of oxytocin all following classical structure-activity profiles of oxytocin. The monocyclic derivatives of [dPen1,Gln4,Lys(CHO)8]oxytocin were antagonists of oxytocin which was attributed to the dPen1 substitution. However, the potency of all of these latter derivatives was at least 1 order of magnitude less than [dPen1,cyclo(Glu4,Lys8)]oxytocin. These results suggest that the potent antagonistic properties of the bicyclic analogues [Mpa1,cyclo(Glu4,Lys8)]oxytocin and [dPen1,cyclo(Glu4,Lys8)]oxytocin can be attributed to the effect of the lactam bridge on the conformational flexibility and topographical properties of the analogues, rendering them more favorable for binding to the receptor in such a manner as to prevent transduction of a biological response.",
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