N-Alkylated derivatives of [D-Pro10]dynorphin A-(1-11) are high affinity partial agonists at the cloned rat κ-opioid receptor

Ken Soderstrom, Heekyung Choi, Frederick W. Berman, Jane V. Aldrich, Thomas F. Murray

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

As part of an effort to develop peptides with selective κ-opioid antagonist activity, a series of N-alkylated [D-Pro10]dynorphin A-(1-11) derivatives were made through solid-phase peptide synthesis: R-Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg-D-Pro-LysOH, where R = N-benzyl, N-cyclopropylmethyl, N,N-dicyclopropylmethyl, or N,N-diallyl. These derivatives and dynorphin A-(1-13)NH2 were evaluated for κ-opioid receptor binding affinity and potency as inhibitors of adenylyl cyclase. Equilibrium competition binding experiments using [3H]diprenorphine( ~ 600 pM) were performed on membranes prepared from cultured Chinese hamster ovary (CHO) cells stably expressing the rat κ-opioid receptor. Tissue prepared from this cell line was used to evaluate opioid peptide inhibition of forskolin-stimulated (50 μM) adenylyl cyclase activity. Displacement of [3H]diprenorphine specific binding by these peptides was observed with a rank order of affinity (K(i), nM)= [D-Pro10]dynorphin A-(1-11) (0.13)> dynorphin A-(1-13)NH2 (0.34)> N-cyclopropylmethyl- (1.4)> N,N-dicyclopropylmethyl- (12.6) ~ N-benzyl- (18.3)~ N,N-diallyl-[D-Pro10]dynorphin A-(1-11) (26.0). A similar rank order was observed for potency of adenylyl cyclase inhibition (IC50, nM): [D-Pro10]dynorphin A-(1-11) (0.12)~ dynorphin A-(1 -13)NH2 (0.19) > N-cyclopropylmethyl- (2.7) > N,N-dicyclopropylmethyl- (13.2) ~ N,N-diallyl- (18.0) ~ N-benzyl-[D-Pro10]dynorphin A-(1-11) (36.4). The peptides differed in their percent maximal inhibition of adenylyl cyclase activity: dynorphin A-(1-13)NH2 (100%)~ N-cyclopropylmethyl- (94.3%)~ [D-Pro10]dynorphin A-(1-11) (87.9%)> N-benzyl- (71.4%) >> N,N-dicyclopropylmethyl- (23.6%)~ N,N-diallyl-[D-Pro10]dynorphin A-(1-11) (18.9%), As the N,N-dicyclopropylmethyl- and N,N-diallyl [D-Pro10]dynorphin A-(1-11) derivatives were found to have only weak partial agonist activity with respect to adenylyl cyclase inhibition, they were evaluated for their ability to reverse dynorphin A-(1-13)NH2 (10 nM) inhibition of adenylyl cyclase activity. N,N-dicyclopropylmetllyl- and N,N-diallyl-[D-Pro10] dynorphin A-(1-11) reversed dynorphin A-(1-13)NH2 inhibition to levels equal to the maximal inhibition produced by N,N-dicyclopropylmethyl- and N,N-diallyl-[D-Pro10]dynorphin A-(1-11) alone. This weak partial agonism combined with nanomolar potency render the N,N-dicyclopropylmethyl- and N,N-diallyl-[D-Pro10]dynorphin A-(1-11) compounds promising leads for further attempts to synthesize peptide κ-opioid receptor antagonists.

Original languageEnglish
Pages (from-to)191-197
Number of pages7
JournalEuropean Journal of Pharmacology
Volume338
Issue number2
DOIs
StatePublished - Nov 5 1997
Externally publishedYes

Fingerprint

Dynorphins
Opioid Receptors
Adenylyl Cyclases
Diprenorphine
Narcotic Antagonists
Peptides
Leucine Enkephalin
Solid-Phase Synthesis Techniques
Peptide Receptors
Opioid Peptides
Colforsin
Cricetulus
Inhibitory Concentration 50
dynorphin (1-13)
Ovary

All Science Journal Classification (ASJC) codes

  • Cellular and Molecular Neuroscience
  • Pharmacology

Cite this

N-Alkylated derivatives of [D-Pro10]dynorphin A-(1-11) are high affinity partial agonists at the cloned rat κ-opioid receptor. / Soderstrom, Ken; Choi, Heekyung; Berman, Frederick W.; Aldrich, Jane V.; Murray, Thomas F.

In: European Journal of Pharmacology, Vol. 338, No. 2, 05.11.1997, p. 191-197.

Research output: Contribution to journalArticle

Soderstrom, Ken ; Choi, Heekyung ; Berman, Frederick W. ; Aldrich, Jane V. ; Murray, Thomas F. / N-Alkylated derivatives of [D-Pro10]dynorphin A-(1-11) are high affinity partial agonists at the cloned rat κ-opioid receptor. In: European Journal of Pharmacology. 1997 ; Vol. 338, No. 2. pp. 191-197.
@article{5171bfb91547499ca4fe6f8cca44cfb2,
title = "N-Alkylated derivatives of [D-Pro10]dynorphin A-(1-11) are high affinity partial agonists at the cloned rat κ-opioid receptor",
abstract = "As part of an effort to develop peptides with selective κ-opioid antagonist activity, a series of N-alkylated [D-Pro10]dynorphin A-(1-11) derivatives were made through solid-phase peptide synthesis: R-Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg-D-Pro-LysOH, where R = N-benzyl, N-cyclopropylmethyl, N,N-dicyclopropylmethyl, or N,N-diallyl. These derivatives and dynorphin A-(1-13)NH2 were evaluated for κ-opioid receptor binding affinity and potency as inhibitors of adenylyl cyclase. Equilibrium competition binding experiments using [3H]diprenorphine( ~ 600 pM) were performed on membranes prepared from cultured Chinese hamster ovary (CHO) cells stably expressing the rat κ-opioid receptor. Tissue prepared from this cell line was used to evaluate opioid peptide inhibition of forskolin-stimulated (50 μM) adenylyl cyclase activity. Displacement of [3H]diprenorphine specific binding by these peptides was observed with a rank order of affinity (K(i), nM)= [D-Pro10]dynorphin A-(1-11) (0.13)> dynorphin A-(1-13)NH2 (0.34)> N-cyclopropylmethyl- (1.4)> N,N-dicyclopropylmethyl- (12.6) ~ N-benzyl- (18.3)~ N,N-diallyl-[D-Pro10]dynorphin A-(1-11) (26.0). A similar rank order was observed for potency of adenylyl cyclase inhibition (IC50, nM): [D-Pro10]dynorphin A-(1-11) (0.12)~ dynorphin A-(1 -13)NH2 (0.19) > N-cyclopropylmethyl- (2.7) > N,N-dicyclopropylmethyl- (13.2) ~ N,N-diallyl- (18.0) ~ N-benzyl-[D-Pro10]dynorphin A-(1-11) (36.4). The peptides differed in their percent maximal inhibition of adenylyl cyclase activity: dynorphin A-(1-13)NH2 (100{\%})~ N-cyclopropylmethyl- (94.3{\%})~ [D-Pro10]dynorphin A-(1-11) (87.9{\%})> N-benzyl- (71.4{\%}) >> N,N-dicyclopropylmethyl- (23.6{\%})~ N,N-diallyl-[D-Pro10]dynorphin A-(1-11) (18.9{\%}), As the N,N-dicyclopropylmethyl- and N,N-diallyl [D-Pro10]dynorphin A-(1-11) derivatives were found to have only weak partial agonist activity with respect to adenylyl cyclase inhibition, they were evaluated for their ability to reverse dynorphin A-(1-13)NH2 (10 nM) inhibition of adenylyl cyclase activity. N,N-dicyclopropylmetllyl- and N,N-diallyl-[D-Pro10] dynorphin A-(1-11) reversed dynorphin A-(1-13)NH2 inhibition to levels equal to the maximal inhibition produced by N,N-dicyclopropylmethyl- and N,N-diallyl-[D-Pro10]dynorphin A-(1-11) alone. This weak partial agonism combined with nanomolar potency render the N,N-dicyclopropylmethyl- and N,N-diallyl-[D-Pro10]dynorphin A-(1-11) compounds promising leads for further attempts to synthesize peptide κ-opioid receptor antagonists.",
author = "Ken Soderstrom and Heekyung Choi and Berman, {Frederick W.} and Aldrich, {Jane V.} and Murray, {Thomas F.}",
year = "1997",
month = "11",
day = "5",
doi = "10.1016/S0014-2999(97)81948-6",
language = "English",
volume = "338",
pages = "191--197",
journal = "European Journal of Pharmacology",
issn = "0014-2999",
publisher = "Elsevier",
number = "2",

}

TY - JOUR

T1 - N-Alkylated derivatives of [D-Pro10]dynorphin A-(1-11) are high affinity partial agonists at the cloned rat κ-opioid receptor

AU - Soderstrom, Ken

AU - Choi, Heekyung

AU - Berman, Frederick W.

AU - Aldrich, Jane V.

AU - Murray, Thomas F.

PY - 1997/11/5

Y1 - 1997/11/5

N2 - As part of an effort to develop peptides with selective κ-opioid antagonist activity, a series of N-alkylated [D-Pro10]dynorphin A-(1-11) derivatives were made through solid-phase peptide synthesis: R-Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg-D-Pro-LysOH, where R = N-benzyl, N-cyclopropylmethyl, N,N-dicyclopropylmethyl, or N,N-diallyl. These derivatives and dynorphin A-(1-13)NH2 were evaluated for κ-opioid receptor binding affinity and potency as inhibitors of adenylyl cyclase. Equilibrium competition binding experiments using [3H]diprenorphine( ~ 600 pM) were performed on membranes prepared from cultured Chinese hamster ovary (CHO) cells stably expressing the rat κ-opioid receptor. Tissue prepared from this cell line was used to evaluate opioid peptide inhibition of forskolin-stimulated (50 μM) adenylyl cyclase activity. Displacement of [3H]diprenorphine specific binding by these peptides was observed with a rank order of affinity (K(i), nM)= [D-Pro10]dynorphin A-(1-11) (0.13)> dynorphin A-(1-13)NH2 (0.34)> N-cyclopropylmethyl- (1.4)> N,N-dicyclopropylmethyl- (12.6) ~ N-benzyl- (18.3)~ N,N-diallyl-[D-Pro10]dynorphin A-(1-11) (26.0). A similar rank order was observed for potency of adenylyl cyclase inhibition (IC50, nM): [D-Pro10]dynorphin A-(1-11) (0.12)~ dynorphin A-(1 -13)NH2 (0.19) > N-cyclopropylmethyl- (2.7) > N,N-dicyclopropylmethyl- (13.2) ~ N,N-diallyl- (18.0) ~ N-benzyl-[D-Pro10]dynorphin A-(1-11) (36.4). The peptides differed in their percent maximal inhibition of adenylyl cyclase activity: dynorphin A-(1-13)NH2 (100%)~ N-cyclopropylmethyl- (94.3%)~ [D-Pro10]dynorphin A-(1-11) (87.9%)> N-benzyl- (71.4%) >> N,N-dicyclopropylmethyl- (23.6%)~ N,N-diallyl-[D-Pro10]dynorphin A-(1-11) (18.9%), As the N,N-dicyclopropylmethyl- and N,N-diallyl [D-Pro10]dynorphin A-(1-11) derivatives were found to have only weak partial agonist activity with respect to adenylyl cyclase inhibition, they were evaluated for their ability to reverse dynorphin A-(1-13)NH2 (10 nM) inhibition of adenylyl cyclase activity. N,N-dicyclopropylmetllyl- and N,N-diallyl-[D-Pro10] dynorphin A-(1-11) reversed dynorphin A-(1-13)NH2 inhibition to levels equal to the maximal inhibition produced by N,N-dicyclopropylmethyl- and N,N-diallyl-[D-Pro10]dynorphin A-(1-11) alone. This weak partial agonism combined with nanomolar potency render the N,N-dicyclopropylmethyl- and N,N-diallyl-[D-Pro10]dynorphin A-(1-11) compounds promising leads for further attempts to synthesize peptide κ-opioid receptor antagonists.

AB - As part of an effort to develop peptides with selective κ-opioid antagonist activity, a series of N-alkylated [D-Pro10]dynorphin A-(1-11) derivatives were made through solid-phase peptide synthesis: R-Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg-D-Pro-LysOH, where R = N-benzyl, N-cyclopropylmethyl, N,N-dicyclopropylmethyl, or N,N-diallyl. These derivatives and dynorphin A-(1-13)NH2 were evaluated for κ-opioid receptor binding affinity and potency as inhibitors of adenylyl cyclase. Equilibrium competition binding experiments using [3H]diprenorphine( ~ 600 pM) were performed on membranes prepared from cultured Chinese hamster ovary (CHO) cells stably expressing the rat κ-opioid receptor. Tissue prepared from this cell line was used to evaluate opioid peptide inhibition of forskolin-stimulated (50 μM) adenylyl cyclase activity. Displacement of [3H]diprenorphine specific binding by these peptides was observed with a rank order of affinity (K(i), nM)= [D-Pro10]dynorphin A-(1-11) (0.13)> dynorphin A-(1-13)NH2 (0.34)> N-cyclopropylmethyl- (1.4)> N,N-dicyclopropylmethyl- (12.6) ~ N-benzyl- (18.3)~ N,N-diallyl-[D-Pro10]dynorphin A-(1-11) (26.0). A similar rank order was observed for potency of adenylyl cyclase inhibition (IC50, nM): [D-Pro10]dynorphin A-(1-11) (0.12)~ dynorphin A-(1 -13)NH2 (0.19) > N-cyclopropylmethyl- (2.7) > N,N-dicyclopropylmethyl- (13.2) ~ N,N-diallyl- (18.0) ~ N-benzyl-[D-Pro10]dynorphin A-(1-11) (36.4). The peptides differed in their percent maximal inhibition of adenylyl cyclase activity: dynorphin A-(1-13)NH2 (100%)~ N-cyclopropylmethyl- (94.3%)~ [D-Pro10]dynorphin A-(1-11) (87.9%)> N-benzyl- (71.4%) >> N,N-dicyclopropylmethyl- (23.6%)~ N,N-diallyl-[D-Pro10]dynorphin A-(1-11) (18.9%), As the N,N-dicyclopropylmethyl- and N,N-diallyl [D-Pro10]dynorphin A-(1-11) derivatives were found to have only weak partial agonist activity with respect to adenylyl cyclase inhibition, they were evaluated for their ability to reverse dynorphin A-(1-13)NH2 (10 nM) inhibition of adenylyl cyclase activity. N,N-dicyclopropylmetllyl- and N,N-diallyl-[D-Pro10] dynorphin A-(1-11) reversed dynorphin A-(1-13)NH2 inhibition to levels equal to the maximal inhibition produced by N,N-dicyclopropylmethyl- and N,N-diallyl-[D-Pro10]dynorphin A-(1-11) alone. This weak partial agonism combined with nanomolar potency render the N,N-dicyclopropylmethyl- and N,N-diallyl-[D-Pro10]dynorphin A-(1-11) compounds promising leads for further attempts to synthesize peptide κ-opioid receptor antagonists.

UR - http://www.scopus.com/inward/record.url?scp=0030725913&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0030725913&partnerID=8YFLogxK

U2 - 10.1016/S0014-2999(97)81948-6

DO - 10.1016/S0014-2999(97)81948-6

M3 - Article

VL - 338

SP - 191

EP - 197

JO - European Journal of Pharmacology

JF - European Journal of Pharmacology

SN - 0014-2999

IS - 2

ER -