Ring substituted and other conformationally constrained tyrosine analogues of [D-Pen2,D-Pen5]enkephalin with δ opioid receptor selectivity

Geza Toth, K. C. Russell, Geoffrey Landis, Thomas H. Kramer, Lei Fang, Richard Knapp, Peg Davis, Thomas F. Burks, Victor J Hruby, Victor J. Hruby

Research output: Contribution to journalArticle

73 Citations (Scopus)

Abstract

The conformationally restricted, cyclic disulfide-containing δ opioid receptor selective enkephalin analogue [D-Pen2,D-Pen5]enkephalin (DPDPE) was modified by 2′ (CH3) and 3′ (I, OCH3, NO2, NH2) ring substitutions and by β-methyl conformationally constrained β-methyltyrosine derivatives in the 1 position. The potency and selectivity of these analogues were evaluated by bioassay in the mouse vas deference (MVD, δ receptor assay) and guinea pig ileum (GPI, μ receptor assay) assays and by radioreceptor binding assays in the rat brain using [3H]CTOP (μ ligand) and [3H][p-ClPhe4]DPDPE (δ ligand). The analogues showed highly variable potencies in the binding assays and in the bioassays. Aromatic ring substituents with positive Hammett constants had decreased potency, while substituents with negative Hammett constants has increased potency for the opioid receptor. The most potent and most selective compound based on the binding was [2′-MeTyr1]DPDPE (IC50 = 0.89 nM and selectivity ratio 1310 in the binding assays). The 6-hydroxy-2-aminotetralin-2-carboxylic acid-containing analogue, [Hat1]DPDPE, also was highly potent and selective in both assays, demonstrating that significant modifications of tyrosine in enkephalins are possible with maintenance of high potency and δ opioid receptor selectivity. Of the β-methyl-substituted Tyr1 analogues, [(2S,3R)-β-MeTyr1]DPDPE was the most potent and δ receptor selective. The results with substitution of β-MeTyr or Hat instead of Tyr also demonstrate that topographical modification in a conformationally restricted ligand can significantly modulate both potency and receptor selectivity of peptide ligands that have multiple sites of biological activity.

Original languageEnglish (US)
Pages (from-to)2384-2391
Number of pages8
JournalJournal of Medicinal Chemistry
Volume35
Issue number13
StatePublished - 1992

Fingerprint

D-Penicillamine (2,5)-Enkephalin
Opioid Receptors
Tyrosine
Assays
Ligands
Enkephalins
Biological Assay
Methyltyrosines
Bioassay
Radioligand Assay
Peptide Receptors
Substitution reactions
Ileum
Disulfides
Inhibitory Concentration 50
Guinea Pigs
Bioactivity
Rats
Brain
Derivatives

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Toth, G., Russell, K. C., Landis, G., Kramer, T. H., Fang, L., Knapp, R., ... Hruby, V. J. (1992). Ring substituted and other conformationally constrained tyrosine analogues of [D-Pen2,D-Pen5]enkephalin with δ opioid receptor selectivity. Journal of Medicinal Chemistry, 35(13), 2384-2391.

Ring substituted and other conformationally constrained tyrosine analogues of [D-Pen2,D-Pen5]enkephalin with δ opioid receptor selectivity. / Toth, Geza; Russell, K. C.; Landis, Geoffrey; Kramer, Thomas H.; Fang, Lei; Knapp, Richard; Davis, Peg; Burks, Thomas F.; Hruby, Victor J; Hruby, Victor J.

In: Journal of Medicinal Chemistry, Vol. 35, No. 13, 1992, p. 2384-2391.

Research output: Contribution to journalArticle

Toth, G, Russell, KC, Landis, G, Kramer, TH, Fang, L, Knapp, R, Davis, P, Burks, TF, Hruby, VJ & Hruby, VJ 1992, 'Ring substituted and other conformationally constrained tyrosine analogues of [D-Pen2,D-Pen5]enkephalin with δ opioid receptor selectivity', Journal of Medicinal Chemistry, vol. 35, no. 13, pp. 2384-2391.
Toth, Geza ; Russell, K. C. ; Landis, Geoffrey ; Kramer, Thomas H. ; Fang, Lei ; Knapp, Richard ; Davis, Peg ; Burks, Thomas F. ; Hruby, Victor J ; Hruby, Victor J. / Ring substituted and other conformationally constrained tyrosine analogues of [D-Pen2,D-Pen5]enkephalin with δ opioid receptor selectivity. In: Journal of Medicinal Chemistry. 1992 ; Vol. 35, No. 13. pp. 2384-2391.
@article{83b224e6ddb5478b9b80a56126f23ebf,
title = "Ring substituted and other conformationally constrained tyrosine analogues of [D-Pen2,D-Pen5]enkephalin with δ opioid receptor selectivity",
abstract = "The conformationally restricted, cyclic disulfide-containing δ opioid receptor selective enkephalin analogue [D-Pen2,D-Pen5]enkephalin (DPDPE) was modified by 2′ (CH3) and 3′ (I, OCH3, NO2, NH2) ring substitutions and by β-methyl conformationally constrained β-methyltyrosine derivatives in the 1 position. The potency and selectivity of these analogues were evaluated by bioassay in the mouse vas deference (MVD, δ receptor assay) and guinea pig ileum (GPI, μ receptor assay) assays and by radioreceptor binding assays in the rat brain using [3H]CTOP (μ ligand) and [3H][p-ClPhe4]DPDPE (δ ligand). The analogues showed highly variable potencies in the binding assays and in the bioassays. Aromatic ring substituents with positive Hammett constants had decreased potency, while substituents with negative Hammett constants has increased potency for the opioid receptor. The most potent and most selective compound based on the binding was [2′-MeTyr1]DPDPE (IC50 = 0.89 nM and selectivity ratio 1310 in the binding assays). The 6-hydroxy-2-aminotetralin-2-carboxylic acid-containing analogue, [Hat1]DPDPE, also was highly potent and selective in both assays, demonstrating that significant modifications of tyrosine in enkephalins are possible with maintenance of high potency and δ opioid receptor selectivity. Of the β-methyl-substituted Tyr1 analogues, [(2S,3R)-β-MeTyr1]DPDPE was the most potent and δ receptor selective. The results with substitution of β-MeTyr or Hat instead of Tyr also demonstrate that topographical modification in a conformationally restricted ligand can significantly modulate both potency and receptor selectivity of peptide ligands that have multiple sites of biological activity.",
author = "Geza Toth and Russell, {K. C.} and Geoffrey Landis and Kramer, {Thomas H.} and Lei Fang and Richard Knapp and Peg Davis and Burks, {Thomas F.} and Hruby, {Victor J} and Hruby, {Victor J.}",
year = "1992",
language = "English (US)",
volume = "35",
pages = "2384--2391",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "13",

}

TY - JOUR

T1 - Ring substituted and other conformationally constrained tyrosine analogues of [D-Pen2,D-Pen5]enkephalin with δ opioid receptor selectivity

AU - Toth, Geza

AU - Russell, K. C.

AU - Landis, Geoffrey

AU - Kramer, Thomas H.

AU - Fang, Lei

AU - Knapp, Richard

AU - Davis, Peg

AU - Burks, Thomas F.

AU - Hruby, Victor J

AU - Hruby, Victor J.

PY - 1992

Y1 - 1992

N2 - The conformationally restricted, cyclic disulfide-containing δ opioid receptor selective enkephalin analogue [D-Pen2,D-Pen5]enkephalin (DPDPE) was modified by 2′ (CH3) and 3′ (I, OCH3, NO2, NH2) ring substitutions and by β-methyl conformationally constrained β-methyltyrosine derivatives in the 1 position. The potency and selectivity of these analogues were evaluated by bioassay in the mouse vas deference (MVD, δ receptor assay) and guinea pig ileum (GPI, μ receptor assay) assays and by radioreceptor binding assays in the rat brain using [3H]CTOP (μ ligand) and [3H][p-ClPhe4]DPDPE (δ ligand). The analogues showed highly variable potencies in the binding assays and in the bioassays. Aromatic ring substituents with positive Hammett constants had decreased potency, while substituents with negative Hammett constants has increased potency for the opioid receptor. The most potent and most selective compound based on the binding was [2′-MeTyr1]DPDPE (IC50 = 0.89 nM and selectivity ratio 1310 in the binding assays). The 6-hydroxy-2-aminotetralin-2-carboxylic acid-containing analogue, [Hat1]DPDPE, also was highly potent and selective in both assays, demonstrating that significant modifications of tyrosine in enkephalins are possible with maintenance of high potency and δ opioid receptor selectivity. Of the β-methyl-substituted Tyr1 analogues, [(2S,3R)-β-MeTyr1]DPDPE was the most potent and δ receptor selective. The results with substitution of β-MeTyr or Hat instead of Tyr also demonstrate that topographical modification in a conformationally restricted ligand can significantly modulate both potency and receptor selectivity of peptide ligands that have multiple sites of biological activity.

AB - The conformationally restricted, cyclic disulfide-containing δ opioid receptor selective enkephalin analogue [D-Pen2,D-Pen5]enkephalin (DPDPE) was modified by 2′ (CH3) and 3′ (I, OCH3, NO2, NH2) ring substitutions and by β-methyl conformationally constrained β-methyltyrosine derivatives in the 1 position. The potency and selectivity of these analogues were evaluated by bioassay in the mouse vas deference (MVD, δ receptor assay) and guinea pig ileum (GPI, μ receptor assay) assays and by radioreceptor binding assays in the rat brain using [3H]CTOP (μ ligand) and [3H][p-ClPhe4]DPDPE (δ ligand). The analogues showed highly variable potencies in the binding assays and in the bioassays. Aromatic ring substituents with positive Hammett constants had decreased potency, while substituents with negative Hammett constants has increased potency for the opioid receptor. The most potent and most selective compound based on the binding was [2′-MeTyr1]DPDPE (IC50 = 0.89 nM and selectivity ratio 1310 in the binding assays). The 6-hydroxy-2-aminotetralin-2-carboxylic acid-containing analogue, [Hat1]DPDPE, also was highly potent and selective in both assays, demonstrating that significant modifications of tyrosine in enkephalins are possible with maintenance of high potency and δ opioid receptor selectivity. Of the β-methyl-substituted Tyr1 analogues, [(2S,3R)-β-MeTyr1]DPDPE was the most potent and δ receptor selective. The results with substitution of β-MeTyr or Hat instead of Tyr also demonstrate that topographical modification in a conformationally restricted ligand can significantly modulate both potency and receptor selectivity of peptide ligands that have multiple sites of biological activity.

UR - http://www.scopus.com/inward/record.url?scp=0026647625&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0026647625&partnerID=8YFLogxK

M3 - Article

C2 - 1320122

AN - SCOPUS:0026647625

VL - 35

SP - 2384

EP - 2391

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 13

ER -