Design, synthesis, and biological properties of highly potent cyclic dynorphin a analogues. Analogues cyclized between positions 5 and 111

Meyer Jean-Philippe, Nathan Collins, Lung Feng-Di, Peg Davis, Teresa Zalewska, Frank Porreca, Henry I. Yamamura, Victor J Hruby

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

We have recently reported the synthesis of several cyclic disulfide bridge-containing peptide analogues of dynorphin A (Dyn A), which were conformationally constrained in the putative address segment of the opioid ligand. Several of these analogues, bridged between positions 5 and 11 of Dyn A1-11-NH2, exhibited unexpected selectivities for the κ and μ receptors of the central over the peripheral nervous systems. In order to further investigate the conformational and topographical requirements for the residues in positions 5 and 11 of these analogues, we have synthesized a systematic series of Dyn A1-11-NH2 analogues incorporating the sulfydryl containing amino acids L- and D-Cys and L- and D-Pen in positions 5 and 11, thus producing 16 cyclic peptides. In addition, Dyn A1-11-NH2, [D-Leu5]Dyn A1-11-NH2, and [D-Lys11]Dyn A1-11NH2 were synthesized as standards. Several of these cyclic analogues, especially c[Cys5, D-Cys11] Dyn A1-11-NH2) c[Cys5, L- or D-Pen11]Dyn A1-11-NH2, c[Pen5, L-Pen11]Dyn A1-11-NH2 and c[Pen5, L- or D-Cys11]Dyn A1-11-NH2, retained the same affinity and selectivity (vs theμ and δ receptors) as the parent compound Dyn A1-11-NH2 in the guinea pig brain (GPB). These same analogues and most others exhibited a much lower activity in the guinea pig ileum (GPI), thus leading to centrally vs peripherally selective peptides, but showed a different structure-activity relationship than found previously. In a wider scope, this series of analogues also provided new insights into which amino acids (and their configurations) may be used in positions 5 and 11 of Dyn A analogues for high potency and good selectivity at κ opioid receptors. The results obtained in the GPB suggest that requirements for binding are not the same for the κ, μ, or δ central receptors.

Original languageEnglish (US)
Pages (from-to)3910-3917
Number of pages8
JournalJournal of Medicinal Chemistry
Volume37
Issue number23
StatePublished - 1994

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Dynorphins
Brain
Guinea Pigs
Amino Acids
Cyclic Peptides
Peptides
Neurology
Opioid Receptors
Disulfides
Opioid Analgesics
Peripheral Nervous System
Structure-Activity Relationship
Ligands
Ileum

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Design, synthesis, and biological properties of highly potent cyclic dynorphin a analogues. Analogues cyclized between positions 5 and 111. / Jean-Philippe, Meyer; Collins, Nathan; Feng-Di, Lung; Davis, Peg; Zalewska, Teresa; Porreca, Frank; Yamamura, Henry I.; Hruby, Victor J.

In: Journal of Medicinal Chemistry, Vol. 37, No. 23, 1994, p. 3910-3917.

Research output: Contribution to journalArticle

Jean-Philippe, Meyer ; Collins, Nathan ; Feng-Di, Lung ; Davis, Peg ; Zalewska, Teresa ; Porreca, Frank ; Yamamura, Henry I. ; Hruby, Victor J. / Design, synthesis, and biological properties of highly potent cyclic dynorphin a analogues. Analogues cyclized between positions 5 and 111. In: Journal of Medicinal Chemistry. 1994 ; Vol. 37, No. 23. pp. 3910-3917.
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abstract = "We have recently reported the synthesis of several cyclic disulfide bridge-containing peptide analogues of dynorphin A (Dyn A), which were conformationally constrained in the putative address segment of the opioid ligand. Several of these analogues, bridged between positions 5 and 11 of Dyn A1-11-NH2, exhibited unexpected selectivities for the κ and μ receptors of the central over the peripheral nervous systems. In order to further investigate the conformational and topographical requirements for the residues in positions 5 and 11 of these analogues, we have synthesized a systematic series of Dyn A1-11-NH2 analogues incorporating the sulfydryl containing amino acids L- and D-Cys and L- and D-Pen in positions 5 and 11, thus producing 16 cyclic peptides. In addition, Dyn A1-11-NH2, [D-Leu5]Dyn A1-11-NH2, and [D-Lys11]Dyn A1-11NH2 were synthesized as standards. Several of these cyclic analogues, especially c[Cys5, D-Cys11] Dyn A1-11-NH2) c[Cys5, L- or D-Pen11]Dyn A1-11-NH2, c[Pen5, L-Pen11]Dyn A1-11-NH2 and c[Pen5, L- or D-Cys11]Dyn A1-11-NH2, retained the same affinity and selectivity (vs theμ and δ receptors) as the parent compound Dyn A1-11-NH2 in the guinea pig brain (GPB). These same analogues and most others exhibited a much lower activity in the guinea pig ileum (GPI), thus leading to centrally vs peripherally selective peptides, but showed a different structure-activity relationship than found previously. In a wider scope, this series of analogues also provided new insights into which amino acids (and their configurations) may be used in positions 5 and 11 of Dyn A analogues for high potency and good selectivity at κ opioid receptors. The results obtained in the GPB suggest that requirements for binding are not the same for the κ, μ, or δ central receptors.",
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T1 - Design, synthesis, and biological properties of highly potent cyclic dynorphin a analogues. Analogues cyclized between positions 5 and 111

AU - Jean-Philippe, Meyer

AU - Collins, Nathan

AU - Feng-Di, Lung

AU - Davis, Peg

AU - Zalewska, Teresa

AU - Porreca, Frank

AU - Yamamura, Henry I.

AU - Hruby, Victor J

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