Opiate aromatic pharmacophore structure-activity relationships in CTAP analogues determined by topographical bias, two-dimensional NMR, and biological activity assays

G. Gregg Bonner, Peg Davis, Dagmar Stropova, Sidney Edsall, Henry I. Yamamura, Frank Porreca, Victor J Hruby

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Abstract

Topographically constrained analogues of the highly μ-opioid-receptor- selective antagonist CTAP (H-D-Phe-c[Cys-Tyr-D-Trp-Arg-Thr-Pen]-Thr-NH2, 1) were prepared by solid-phase peptide synthesis. Replacement of the D-Phe residue with conformationally biased β-methyl derivatives of phenylalanine or tryptophan (2R,3R; 2R,3S; 2S,3R; 2S,3S) yielded peptides that displayed widely varying types of biological activities. In an effort to correlate the observed biological activities of these analogues with their structures, two- dimensional 1H NMR and molecular modeling was performed. Unlike the parent (1), which is essentially a pure μ antagonist with weak δ agonist activities in the MVD bioassay, the diastereomeric β-MePhe1-containing peptides exhibited simultaneous δ agonism and μ antagonism by the (2R,3R)- containing isomer 2; μ antagonism by the (2R,3S)-containing isomer 3; weak μ agonism by the (2S,3R)-containing isomer 4; and δ agonism by the (2S,3S)- containing isomer 5. Incorporation of β-MeTrp isomers into position i led to peptides that were μ antagonists (2R,3R), 8; (2R,3S), 9, or essentially inactive (<10%) in the MVD and GPI assays (2S,3R), 10; (2S,3S), 11. Interestingly, in vivo antinociceptive activity was predicted by neither MVD nor GPI bioactivity. When D-Trp was incorporated in position 1, the result (7) is a partial, yet relatively potent μ agonist which also displayed weak δ agonist activity. Molecular modeling based on 2D NMR revealed that low energy conformers of peptides with similar biological activities had similar aromatic pharmacophore orientations and interaromatic distances. Peptides that exhibit μ antagonism have interaromatic distances of 7.0-7.9 A and have their amino terminal aromatic moiety pointing in a direction opposite to the direction that the amino terminus points. Peptides with δ opioid activity displayed an interaromatic distance of < 7 Å and had their amino terminal aromatic moiety pointing in the same direction as the amino terminus.

Original languageEnglish (US)
Pages (from-to)569-580
Number of pages12
JournalJournal of Medicinal Chemistry
Volume43
Issue number4
DOIs
StatePublished - 2000

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Opiate Alkaloids
Structure-Activity Relationship
Bioactivity
Biological Assay
Assays
Nuclear magnetic resonance
Isomers
Peptides
cysteinyltyrosine
Molecular modeling
Dilatation and Curettage
Solid-Phase Synthesis Techniques
Opioid Peptides
Narcotic Antagonists
Bioassay
Opioid Receptors
Phenylalanine
Tryptophan
Opioid Analgesics
Derivatives

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Opiate aromatic pharmacophore structure-activity relationships in CTAP analogues determined by topographical bias, two-dimensional NMR, and biological activity assays. / Bonner, G. Gregg; Davis, Peg; Stropova, Dagmar; Edsall, Sidney; Yamamura, Henry I.; Porreca, Frank; Hruby, Victor J.

In: Journal of Medicinal Chemistry, Vol. 43, No. 4, 2000, p. 569-580.

Research output: Contribution to journalArticle

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title = "Opiate aromatic pharmacophore structure-activity relationships in CTAP analogues determined by topographical bias, two-dimensional NMR, and biological activity assays",
abstract = "Topographically constrained analogues of the highly μ-opioid-receptor- selective antagonist CTAP (H-D-Phe-c[Cys-Tyr-D-Trp-Arg-Thr-Pen]-Thr-NH2, 1) were prepared by solid-phase peptide synthesis. Replacement of the D-Phe residue with conformationally biased β-methyl derivatives of phenylalanine or tryptophan (2R,3R; 2R,3S; 2S,3R; 2S,3S) yielded peptides that displayed widely varying types of biological activities. In an effort to correlate the observed biological activities of these analogues with their structures, two- dimensional 1H NMR and molecular modeling was performed. Unlike the parent (1), which is essentially a pure μ antagonist with weak δ agonist activities in the MVD bioassay, the diastereomeric β-MePhe1-containing peptides exhibited simultaneous δ agonism and μ antagonism by the (2R,3R)- containing isomer 2; μ antagonism by the (2R,3S)-containing isomer 3; weak μ agonism by the (2S,3R)-containing isomer 4; and δ agonism by the (2S,3S)- containing isomer 5. Incorporation of β-MeTrp isomers into position i led to peptides that were μ antagonists (2R,3R), 8; (2R,3S), 9, or essentially inactive (<10{\%}) in the MVD and GPI assays (2S,3R), 10; (2S,3S), 11. Interestingly, in vivo antinociceptive activity was predicted by neither MVD nor GPI bioactivity. When D-Trp was incorporated in position 1, the result (7) is a partial, yet relatively potent μ agonist which also displayed weak δ agonist activity. Molecular modeling based on 2D NMR revealed that low energy conformers of peptides with similar biological activities had similar aromatic pharmacophore orientations and interaromatic distances. Peptides that exhibit μ antagonism have interaromatic distances of 7.0-7.9 A and have their amino terminal aromatic moiety pointing in a direction opposite to the direction that the amino terminus points. Peptides with δ opioid activity displayed an interaromatic distance of < 7 {\AA} and had their amino terminal aromatic moiety pointing in the same direction as the amino terminus.",
author = "Bonner, {G. Gregg} and Peg Davis and Dagmar Stropova and Sidney Edsall and Yamamura, {Henry I.} and Frank Porreca and Hruby, {Victor J}",
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T1 - Opiate aromatic pharmacophore structure-activity relationships in CTAP analogues determined by topographical bias, two-dimensional NMR, and biological activity assays

AU - Bonner, G. Gregg

AU - Davis, Peg

AU - Stropova, Dagmar

AU - Edsall, Sidney

AU - Yamamura, Henry I.

AU - Porreca, Frank

AU - Hruby, Victor J

PY - 2000

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N2 - Topographically constrained analogues of the highly μ-opioid-receptor- selective antagonist CTAP (H-D-Phe-c[Cys-Tyr-D-Trp-Arg-Thr-Pen]-Thr-NH2, 1) were prepared by solid-phase peptide synthesis. Replacement of the D-Phe residue with conformationally biased β-methyl derivatives of phenylalanine or tryptophan (2R,3R; 2R,3S; 2S,3R; 2S,3S) yielded peptides that displayed widely varying types of biological activities. In an effort to correlate the observed biological activities of these analogues with their structures, two- dimensional 1H NMR and molecular modeling was performed. Unlike the parent (1), which is essentially a pure μ antagonist with weak δ agonist activities in the MVD bioassay, the diastereomeric β-MePhe1-containing peptides exhibited simultaneous δ agonism and μ antagonism by the (2R,3R)- containing isomer 2; μ antagonism by the (2R,3S)-containing isomer 3; weak μ agonism by the (2S,3R)-containing isomer 4; and δ agonism by the (2S,3S)- containing isomer 5. Incorporation of β-MeTrp isomers into position i led to peptides that were μ antagonists (2R,3R), 8; (2R,3S), 9, or essentially inactive (<10%) in the MVD and GPI assays (2S,3R), 10; (2S,3S), 11. Interestingly, in vivo antinociceptive activity was predicted by neither MVD nor GPI bioactivity. When D-Trp was incorporated in position 1, the result (7) is a partial, yet relatively potent μ agonist which also displayed weak δ agonist activity. Molecular modeling based on 2D NMR revealed that low energy conformers of peptides with similar biological activities had similar aromatic pharmacophore orientations and interaromatic distances. Peptides that exhibit μ antagonism have interaromatic distances of 7.0-7.9 A and have their amino terminal aromatic moiety pointing in a direction opposite to the direction that the amino terminus points. Peptides with δ opioid activity displayed an interaromatic distance of < 7 Å and had their amino terminal aromatic moiety pointing in the same direction as the amino terminus.

AB - Topographically constrained analogues of the highly μ-opioid-receptor- selective antagonist CTAP (H-D-Phe-c[Cys-Tyr-D-Trp-Arg-Thr-Pen]-Thr-NH2, 1) were prepared by solid-phase peptide synthesis. Replacement of the D-Phe residue with conformationally biased β-methyl derivatives of phenylalanine or tryptophan (2R,3R; 2R,3S; 2S,3R; 2S,3S) yielded peptides that displayed widely varying types of biological activities. In an effort to correlate the observed biological activities of these analogues with their structures, two- dimensional 1H NMR and molecular modeling was performed. Unlike the parent (1), which is essentially a pure μ antagonist with weak δ agonist activities in the MVD bioassay, the diastereomeric β-MePhe1-containing peptides exhibited simultaneous δ agonism and μ antagonism by the (2R,3R)- containing isomer 2; μ antagonism by the (2R,3S)-containing isomer 3; weak μ agonism by the (2S,3R)-containing isomer 4; and δ agonism by the (2S,3S)- containing isomer 5. Incorporation of β-MeTrp isomers into position i led to peptides that were μ antagonists (2R,3R), 8; (2R,3S), 9, or essentially inactive (<10%) in the MVD and GPI assays (2S,3R), 10; (2S,3S), 11. Interestingly, in vivo antinociceptive activity was predicted by neither MVD nor GPI bioactivity. When D-Trp was incorporated in position 1, the result (7) is a partial, yet relatively potent μ agonist which also displayed weak δ agonist activity. Molecular modeling based on 2D NMR revealed that low energy conformers of peptides with similar biological activities had similar aromatic pharmacophore orientations and interaromatic distances. Peptides that exhibit μ antagonism have interaromatic distances of 7.0-7.9 A and have their amino terminal aromatic moiety pointing in a direction opposite to the direction that the amino terminus points. Peptides with δ opioid activity displayed an interaromatic distance of < 7 Å and had their amino terminal aromatic moiety pointing in the same direction as the amino terminus.

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