Probing the stereochemical requirements for receptor recognition of δ opioid agonists through topographic modifications in position 1

X. Qian, M. D. Shenderovich, K. Kövér, P. Davis, R. Horvath, T. Zalewska, H. I. Yamamura, F. Porreca, V. J. Hruby

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

A series of side-chain constrained tyrosine derivatives, 2',6'-dimethyl-β-methyltyrosines (TMT), has been designed and incorporated into position 1 of the highly selective δ opioid agonists DPDPE (Tyr-D-Pen2-Gly-Phe-D-Pen5-OH) and deltorphin I (DELT I, Tyr-D-Ala-Phe-Asp-Val-Val-Gly-NH2). Molecular mechanics calculations on isolated TMT residues and nuclear magnetic resonance (NMR) studies of the TMT1-containing peptides in DMSO showed that each of the four stereoisomers of TMT favors one particular rotamer of the side-chain χ1 torsional angle. Therefore, substitution of four TMT isomers for Tyr1 allows us to perform a systematic conformational scan through three staggered rotamers of the aromatic side chain, gauche (-), trans, and gauche (+), and to explore specific binding requirements of the receptor in relation to the side chain conformation. The potency and selectivity of four isomers of [TMT1]DPDPE and four isomers of [TMT1]DELT I were evaluated by radioreceptor binding assays in the rat brain using μ- and δ-selective radiolabeled ligands and by bioassays with guinea pig ileum (GPI, μ receptor) and mouse vas deferens (MVD, δ receptor). In the DPDPE series only one isomer, [(2S,3R)-TMT1 ]DPDPE showed high potency and selectivity for the δ opioid receptors. The favorable side-chain rotamers found for this analogue, i.e., the trans rotamer of TMT1 and the gauche (-) rotamer of Phe4, were proposed as the most probable δ receptor-binding conformations of DPDPE analogues. Two [TMT1]DELT I isomers possessed considerable δ receptor potencies. The (2S,3R)-TMT1 isomer appeared to be a superpotent, but moderately δ-selective agonist, while the (2S,3S)-TMT1 isomer showed the highest selectivity for the δ receptors in this series. Surprisingly, [(2R,3R)TMT1]DELT I also was moderately potent at the δ receptor. These results suggest that the δ receptor requirements for the linear DELT I analogues may be satisfied with two different modes of binding of the (2S,3S)- and (2S,3R)TMT1 isomers. This study provides important guidance for the design of peptide and non-peptide ligands selective for the δ opioid receptor.

Original languageEnglish
Pages (from-to)7280-7290
Number of pages11
JournalJournal of the American Chemical Society
Volume118
Issue number31
DOIs
Publication statusPublished - 1996

Fingerprint

glycylphenylalanine
Opioid Receptors
Isomers
Opioid Analgesics
Methyltyrosines
Peptides
Conformations
Ligands
Radioligand Assay
Stereoisomerism
Vas Deferens
Molecular mechanics
Dimethyl Sulfoxide
Ala(2)-deltorphin I
Bioassay
Mechanics
Ileum
Biological Assay
Guinea Pigs
Magnetic Resonance Spectroscopy

ASJC Scopus subject areas

  • Chemistry(all)

Cite this

Probing the stereochemical requirements for receptor recognition of δ opioid agonists through topographic modifications in position 1. / Qian, X.; Shenderovich, M. D.; Kövér, K.; Davis, P.; Horvath, R.; Zalewska, T.; Yamamura, H. I.; Porreca, F.; Hruby, V. J.

In: Journal of the American Chemical Society, Vol. 118, No. 31, 1996, p. 7280-7290.

Research output: Contribution to journalArticle

Qian, X. ; Shenderovich, M. D. ; Kövér, K. ; Davis, P. ; Horvath, R. ; Zalewska, T. ; Yamamura, H. I. ; Porreca, F. ; Hruby, V. J. / Probing the stereochemical requirements for receptor recognition of δ opioid agonists through topographic modifications in position 1. In: Journal of the American Chemical Society. 1996 ; Vol. 118, No. 31. pp. 7280-7290.
@article{7622ee2cc63b4ac0a47d419ca4b796b3,
title = "Probing the stereochemical requirements for receptor recognition of δ opioid agonists through topographic modifications in position 1",
abstract = "A series of side-chain constrained tyrosine derivatives, 2',6'-dimethyl-β-methyltyrosines (TMT), has been designed and incorporated into position 1 of the highly selective δ opioid agonists DPDPE (Tyr-D-Pen2-Gly-Phe-D-Pen5-OH) and deltorphin I (DELT I, Tyr-D-Ala-Phe-Asp-Val-Val-Gly-NH2). Molecular mechanics calculations on isolated TMT residues and nuclear magnetic resonance (NMR) studies of the TMT1-containing peptides in DMSO showed that each of the four stereoisomers of TMT favors one particular rotamer of the side-chain χ1 torsional angle. Therefore, substitution of four TMT isomers for Tyr1 allows us to perform a systematic conformational scan through three staggered rotamers of the aromatic side chain, gauche (-), trans, and gauche (+), and to explore specific binding requirements of the receptor in relation to the side chain conformation. The potency and selectivity of four isomers of [TMT1]DPDPE and four isomers of [TMT1]DELT I were evaluated by radioreceptor binding assays in the rat brain using μ- and δ-selective radiolabeled ligands and by bioassays with guinea pig ileum (GPI, μ receptor) and mouse vas deferens (MVD, δ receptor). In the DPDPE series only one isomer, [(2S,3R)-TMT1 ]DPDPE showed high potency and selectivity for the δ opioid receptors. The favorable side-chain rotamers found for this analogue, i.e., the trans rotamer of TMT1 and the gauche (-) rotamer of Phe4, were proposed as the most probable δ receptor-binding conformations of DPDPE analogues. Two [TMT1]DELT I isomers possessed considerable δ receptor potencies. The (2S,3R)-TMT1 isomer appeared to be a superpotent, but moderately δ-selective agonist, while the (2S,3S)-TMT1 isomer showed the highest selectivity for the δ receptors in this series. Surprisingly, [(2R,3R)TMT1]DELT I also was moderately potent at the δ receptor. These results suggest that the δ receptor requirements for the linear DELT I analogues may be satisfied with two different modes of binding of the (2S,3S)- and (2S,3R)TMT1 isomers. This study provides important guidance for the design of peptide and non-peptide ligands selective for the δ opioid receptor.",
author = "X. Qian and Shenderovich, {M. D.} and K. K{\"o}v{\'e}r and P. Davis and R. Horvath and T. Zalewska and Yamamura, {H. I.} and F. Porreca and Hruby, {V. J.}",
year = "1996",
doi = "10.1021/ja954241w",
language = "English",
volume = "118",
pages = "7280--7290",
journal = "Journal of the American Chemical Society",
issn = "0002-7863",
publisher = "American Chemical Society",
number = "31",

}

TY - JOUR

T1 - Probing the stereochemical requirements for receptor recognition of δ opioid agonists through topographic modifications in position 1

AU - Qian, X.

AU - Shenderovich, M. D.

AU - Kövér, K.

AU - Davis, P.

AU - Horvath, R.

AU - Zalewska, T.

AU - Yamamura, H. I.

AU - Porreca, F.

AU - Hruby, V. J.

PY - 1996

Y1 - 1996

N2 - A series of side-chain constrained tyrosine derivatives, 2',6'-dimethyl-β-methyltyrosines (TMT), has been designed and incorporated into position 1 of the highly selective δ opioid agonists DPDPE (Tyr-D-Pen2-Gly-Phe-D-Pen5-OH) and deltorphin I (DELT I, Tyr-D-Ala-Phe-Asp-Val-Val-Gly-NH2). Molecular mechanics calculations on isolated TMT residues and nuclear magnetic resonance (NMR) studies of the TMT1-containing peptides in DMSO showed that each of the four stereoisomers of TMT favors one particular rotamer of the side-chain χ1 torsional angle. Therefore, substitution of four TMT isomers for Tyr1 allows us to perform a systematic conformational scan through three staggered rotamers of the aromatic side chain, gauche (-), trans, and gauche (+), and to explore specific binding requirements of the receptor in relation to the side chain conformation. The potency and selectivity of four isomers of [TMT1]DPDPE and four isomers of [TMT1]DELT I were evaluated by radioreceptor binding assays in the rat brain using μ- and δ-selective radiolabeled ligands and by bioassays with guinea pig ileum (GPI, μ receptor) and mouse vas deferens (MVD, δ receptor). In the DPDPE series only one isomer, [(2S,3R)-TMT1 ]DPDPE showed high potency and selectivity for the δ opioid receptors. The favorable side-chain rotamers found for this analogue, i.e., the trans rotamer of TMT1 and the gauche (-) rotamer of Phe4, were proposed as the most probable δ receptor-binding conformations of DPDPE analogues. Two [TMT1]DELT I isomers possessed considerable δ receptor potencies. The (2S,3R)-TMT1 isomer appeared to be a superpotent, but moderately δ-selective agonist, while the (2S,3S)-TMT1 isomer showed the highest selectivity for the δ receptors in this series. Surprisingly, [(2R,3R)TMT1]DELT I also was moderately potent at the δ receptor. These results suggest that the δ receptor requirements for the linear DELT I analogues may be satisfied with two different modes of binding of the (2S,3S)- and (2S,3R)TMT1 isomers. This study provides important guidance for the design of peptide and non-peptide ligands selective for the δ opioid receptor.

AB - A series of side-chain constrained tyrosine derivatives, 2',6'-dimethyl-β-methyltyrosines (TMT), has been designed and incorporated into position 1 of the highly selective δ opioid agonists DPDPE (Tyr-D-Pen2-Gly-Phe-D-Pen5-OH) and deltorphin I (DELT I, Tyr-D-Ala-Phe-Asp-Val-Val-Gly-NH2). Molecular mechanics calculations on isolated TMT residues and nuclear magnetic resonance (NMR) studies of the TMT1-containing peptides in DMSO showed that each of the four stereoisomers of TMT favors one particular rotamer of the side-chain χ1 torsional angle. Therefore, substitution of four TMT isomers for Tyr1 allows us to perform a systematic conformational scan through three staggered rotamers of the aromatic side chain, gauche (-), trans, and gauche (+), and to explore specific binding requirements of the receptor in relation to the side chain conformation. The potency and selectivity of four isomers of [TMT1]DPDPE and four isomers of [TMT1]DELT I were evaluated by radioreceptor binding assays in the rat brain using μ- and δ-selective radiolabeled ligands and by bioassays with guinea pig ileum (GPI, μ receptor) and mouse vas deferens (MVD, δ receptor). In the DPDPE series only one isomer, [(2S,3R)-TMT1 ]DPDPE showed high potency and selectivity for the δ opioid receptors. The favorable side-chain rotamers found for this analogue, i.e., the trans rotamer of TMT1 and the gauche (-) rotamer of Phe4, were proposed as the most probable δ receptor-binding conformations of DPDPE analogues. Two [TMT1]DELT I isomers possessed considerable δ receptor potencies. The (2S,3R)-TMT1 isomer appeared to be a superpotent, but moderately δ-selective agonist, while the (2S,3S)-TMT1 isomer showed the highest selectivity for the δ receptors in this series. Surprisingly, [(2R,3R)TMT1]DELT I also was moderately potent at the δ receptor. These results suggest that the δ receptor requirements for the linear DELT I analogues may be satisfied with two different modes of binding of the (2S,3S)- and (2S,3R)TMT1 isomers. This study provides important guidance for the design of peptide and non-peptide ligands selective for the δ opioid receptor.

UR - http://www.scopus.com/inward/record.url?scp=0029740203&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0029740203&partnerID=8YFLogxK

U2 - 10.1021/ja954241w

DO - 10.1021/ja954241w

M3 - Article

VL - 118

SP - 7280

EP - 7290

JO - Journal of the American Chemical Society

JF - Journal of the American Chemical Society

SN - 0002-7863

IS - 31

ER -