Synthesis and opioid activity of [D-Pro10]Dynorphin A-(1-11) analogues with N-terminal alkyl substitution

Heekyung Choi, Thomas F. Murray, Gary E. DeLander, William K. Schmidt, Jane V. Aldrich

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Several N-terminal di- and monoalkylated derivatives of [D- Pro10]dynorphin A-(1-11) were synthesized in order to explore the structure-activity relationships for antagonist vs agonist activity at κ- opioid receptors. N,N-Dialkylated and N-monoalkylated (alkyl = allyl, benzyl, and cyclopropylmethyl (CPM)) tyrosine derivatives were prepared from tyrosine tert-butyl ester and the corresponding alkyl halides. [D-Pro10]Dyn A-(2- 11) was prepared by solid phase synthesis using Fmoc-protected amino acids, and the tyrosine derivatives were coupled to the peptide with BOP ((benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate). Both the degree of substitution and the identity of the alkyl group affected κ-receptor affinity, selectivity, and efficacy. All of the N-monoalkylated derivatives exhibited much higher affinity (K(i) <0.05 nM) for κ receptors in the guinea pig cerebellum and greatly enhanced κ-receptor selectivity (K(i) ratio (κ/μ) > 200) compared to the N,N-dialkyl [D-Pro10]Dyn A-(1- 11) analogues, although one disubstituted analogue, N,N-diCPM[D-Pro10]Dyn A-(1-11), retained high affinity (K(i) = 0.19 nM) for κ receptors. Thus the introduction of the second alkyl group at the N-terminus lowered κ-receptor affinity and selectivity. The N-allyl and N-CPM analogues were moderately potent agonists in the guinea pig ileum (GPI) assay, while the N-benzyl derivative was a weak agonist in this assay. In vivo in the phenylqninone abdominal stretching assay the N-CPM analogue exhibited potent antinociceptive activity (ED50 = 1.1 μg/mouse), while N-allyl[D- Pro10]Dyn A-(l-11) exhibited weak antinociceptive activity (ED50 = 27 μg/mouse). For the N,N-dialkyl derivatives the identity of the N-terminal alkyl group affected the efficacy observed in the smooth muscle assays. The N,N-diCPM analogue exhibited negligible agonist activity, and N,N-diallyl[D- Pro10]Dyn A-(l-11) showed weak antagonist activity against Dyn A-(1- 13)NH2 in the GPI. In contrast, the N,N-dibenzyl compound showed appreciable opioid agonist activity in this assay. In vivo the N,N-diallyl analogue exhibited weak antinociceptive activity (ED50 = 26 μg/mouse in the phenylquinone abdominal stretching assay). The N-monoalkylated peptides are among the most κ-selective opioid peptides reported to date, showing comparable or greater selectivity and higher affinity than the κ-selective nonpeptide agonists U-50,488 and U-69,593. The N,N-diCPM and N,N-diallyl peptides are lead compounds in the development of peptide-based κ-receptor antagonists.

Original languageEnglish
Pages (from-to)2733-2739
Number of pages7
JournalJournal of Medicinal Chemistry
Volume40
Issue number17
DOIs
StatePublished - Aug 15 1997
Externally publishedYes

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Dynorphins
Opioid Analgesics
Tyrosine
Assays
Substitution reactions
Derivatives
Ileum
Peptides
Guinea Pigs
Solid-Phase Synthesis Techniques
Peptide Receptors
Opioid Peptides
Opioid Receptors
Structure-Activity Relationship
Stretching
Smooth Muscle
Esters
Lead compounds
Amino Acids
Muscle

All Science Journal Classification (ASJC) codes

  • Organic Chemistry

Cite this

Synthesis and opioid activity of [D-Pro10]Dynorphin A-(1-11) analogues with N-terminal alkyl substitution. / Choi, Heekyung; Murray, Thomas F.; DeLander, Gary E.; Schmidt, William K.; Aldrich, Jane V.

In: Journal of Medicinal Chemistry, Vol. 40, No. 17, 15.08.1997, p. 2733-2739.

Research output: Contribution to journalArticle

Choi, Heekyung ; Murray, Thomas F. ; DeLander, Gary E. ; Schmidt, William K. ; Aldrich, Jane V. / Synthesis and opioid activity of [D-Pro10]Dynorphin A-(1-11) analogues with N-terminal alkyl substitution. In: Journal of Medicinal Chemistry. 1997 ; Vol. 40, No. 17. pp. 2733-2739.
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abstract = "Several N-terminal di- and monoalkylated derivatives of [D- Pro10]dynorphin A-(1-11) were synthesized in order to explore the structure-activity relationships for antagonist vs agonist activity at κ- opioid receptors. N,N-Dialkylated and N-monoalkylated (alkyl = allyl, benzyl, and cyclopropylmethyl (CPM)) tyrosine derivatives were prepared from tyrosine tert-butyl ester and the corresponding alkyl halides. [D-Pro10]Dyn A-(2- 11) was prepared by solid phase synthesis using Fmoc-protected amino acids, and the tyrosine derivatives were coupled to the peptide with BOP ((benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate). Both the degree of substitution and the identity of the alkyl group affected κ-receptor affinity, selectivity, and efficacy. All of the N-monoalkylated derivatives exhibited much higher affinity (K(i) <0.05 nM) for κ receptors in the guinea pig cerebellum and greatly enhanced κ-receptor selectivity (K(i) ratio (κ/μ) > 200) compared to the N,N-dialkyl [D-Pro10]Dyn A-(1- 11) analogues, although one disubstituted analogue, N,N-diCPM[D-Pro10]Dyn A-(1-11), retained high affinity (K(i) = 0.19 nM) for κ receptors. Thus the introduction of the second alkyl group at the N-terminus lowered κ-receptor affinity and selectivity. The N-allyl and N-CPM analogues were moderately potent agonists in the guinea pig ileum (GPI) assay, while the N-benzyl derivative was a weak agonist in this assay. In vivo in the phenylqninone abdominal stretching assay the N-CPM analogue exhibited potent antinociceptive activity (ED50 = 1.1 μg/mouse), while N-allyl[D- Pro10]Dyn A-(l-11) exhibited weak antinociceptive activity (ED50 = 27 μg/mouse). For the N,N-dialkyl derivatives the identity of the N-terminal alkyl group affected the efficacy observed in the smooth muscle assays. The N,N-diCPM analogue exhibited negligible agonist activity, and N,N-diallyl[D- Pro10]Dyn A-(l-11) showed weak antagonist activity against Dyn A-(1- 13)NH2 in the GPI. In contrast, the N,N-dibenzyl compound showed appreciable opioid agonist activity in this assay. In vivo the N,N-diallyl analogue exhibited weak antinociceptive activity (ED50 = 26 μg/mouse in the phenylquinone abdominal stretching assay). The N-monoalkylated peptides are among the most κ-selective opioid peptides reported to date, showing comparable or greater selectivity and higher affinity than the κ-selective nonpeptide agonists U-50,488 and U-69,593. The N,N-diCPM and N,N-diallyl peptides are lead compounds in the development of peptide-based κ-receptor antagonists.",
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T1 - Synthesis and opioid activity of [D-Pro10]Dynorphin A-(1-11) analogues with N-terminal alkyl substitution

AU - Choi, Heekyung

AU - Murray, Thomas F.

AU - DeLander, Gary E.

AU - Schmidt, William K.

AU - Aldrich, Jane V.

PY - 1997/8/15

Y1 - 1997/8/15

N2 - Several N-terminal di- and monoalkylated derivatives of [D- Pro10]dynorphin A-(1-11) were synthesized in order to explore the structure-activity relationships for antagonist vs agonist activity at κ- opioid receptors. N,N-Dialkylated and N-monoalkylated (alkyl = allyl, benzyl, and cyclopropylmethyl (CPM)) tyrosine derivatives were prepared from tyrosine tert-butyl ester and the corresponding alkyl halides. [D-Pro10]Dyn A-(2- 11) was prepared by solid phase synthesis using Fmoc-protected amino acids, and the tyrosine derivatives were coupled to the peptide with BOP ((benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate). Both the degree of substitution and the identity of the alkyl group affected κ-receptor affinity, selectivity, and efficacy. All of the N-monoalkylated derivatives exhibited much higher affinity (K(i) <0.05 nM) for κ receptors in the guinea pig cerebellum and greatly enhanced κ-receptor selectivity (K(i) ratio (κ/μ) > 200) compared to the N,N-dialkyl [D-Pro10]Dyn A-(1- 11) analogues, although one disubstituted analogue, N,N-diCPM[D-Pro10]Dyn A-(1-11), retained high affinity (K(i) = 0.19 nM) for κ receptors. Thus the introduction of the second alkyl group at the N-terminus lowered κ-receptor affinity and selectivity. The N-allyl and N-CPM analogues were moderately potent agonists in the guinea pig ileum (GPI) assay, while the N-benzyl derivative was a weak agonist in this assay. In vivo in the phenylqninone abdominal stretching assay the N-CPM analogue exhibited potent antinociceptive activity (ED50 = 1.1 μg/mouse), while N-allyl[D- Pro10]Dyn A-(l-11) exhibited weak antinociceptive activity (ED50 = 27 μg/mouse). For the N,N-dialkyl derivatives the identity of the N-terminal alkyl group affected the efficacy observed in the smooth muscle assays. The N,N-diCPM analogue exhibited negligible agonist activity, and N,N-diallyl[D- Pro10]Dyn A-(l-11) showed weak antagonist activity against Dyn A-(1- 13)NH2 in the GPI. In contrast, the N,N-dibenzyl compound showed appreciable opioid agonist activity in this assay. In vivo the N,N-diallyl analogue exhibited weak antinociceptive activity (ED50 = 26 μg/mouse in the phenylquinone abdominal stretching assay). The N-monoalkylated peptides are among the most κ-selective opioid peptides reported to date, showing comparable or greater selectivity and higher affinity than the κ-selective nonpeptide agonists U-50,488 and U-69,593. The N,N-diCPM and N,N-diallyl peptides are lead compounds in the development of peptide-based κ-receptor antagonists.

AB - Several N-terminal di- and monoalkylated derivatives of [D- Pro10]dynorphin A-(1-11) were synthesized in order to explore the structure-activity relationships for antagonist vs agonist activity at κ- opioid receptors. N,N-Dialkylated and N-monoalkylated (alkyl = allyl, benzyl, and cyclopropylmethyl (CPM)) tyrosine derivatives were prepared from tyrosine tert-butyl ester and the corresponding alkyl halides. [D-Pro10]Dyn A-(2- 11) was prepared by solid phase synthesis using Fmoc-protected amino acids, and the tyrosine derivatives were coupled to the peptide with BOP ((benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate). Both the degree of substitution and the identity of the alkyl group affected κ-receptor affinity, selectivity, and efficacy. All of the N-monoalkylated derivatives exhibited much higher affinity (K(i) <0.05 nM) for κ receptors in the guinea pig cerebellum and greatly enhanced κ-receptor selectivity (K(i) ratio (κ/μ) > 200) compared to the N,N-dialkyl [D-Pro10]Dyn A-(1- 11) analogues, although one disubstituted analogue, N,N-diCPM[D-Pro10]Dyn A-(1-11), retained high affinity (K(i) = 0.19 nM) for κ receptors. Thus the introduction of the second alkyl group at the N-terminus lowered κ-receptor affinity and selectivity. The N-allyl and N-CPM analogues were moderately potent agonists in the guinea pig ileum (GPI) assay, while the N-benzyl derivative was a weak agonist in this assay. In vivo in the phenylqninone abdominal stretching assay the N-CPM analogue exhibited potent antinociceptive activity (ED50 = 1.1 μg/mouse), while N-allyl[D- Pro10]Dyn A-(l-11) exhibited weak antinociceptive activity (ED50 = 27 μg/mouse). For the N,N-dialkyl derivatives the identity of the N-terminal alkyl group affected the efficacy observed in the smooth muscle assays. The N,N-diCPM analogue exhibited negligible agonist activity, and N,N-diallyl[D- Pro10]Dyn A-(l-11) showed weak antagonist activity against Dyn A-(1- 13)NH2 in the GPI. In contrast, the N,N-dibenzyl compound showed appreciable opioid agonist activity in this assay. In vivo the N,N-diallyl analogue exhibited weak antinociceptive activity (ED50 = 26 μg/mouse in the phenylquinone abdominal stretching assay). The N-monoalkylated peptides are among the most κ-selective opioid peptides reported to date, showing comparable or greater selectivity and higher affinity than the κ-selective nonpeptide agonists U-50,488 and U-69,593. The N,N-diCPM and N,N-diallyl peptides are lead compounds in the development of peptide-based κ-receptor antagonists.

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