Delta Opioidmimetic Antagonists: Prototypes for Designing a New Generation of Ultraselective Opioid Peptides

Overview

Journal Mol Med

Publisher Biomed Central

Specialties General Medicine
Molecular Biology

Date 1995 Sep 1

PMID 8529134

Citations 29

Authors

S Salvadori

M Attila

G Balboni

C Bianchi

S D Bryant

O Crescenzi

R Guerrini

D Picone

T Tancredi

P A Temussi

Affiliations

Soon will be listed here.

Abstract

Background: Tyr-Tic (1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) and Tyr-Tic-Ala were the first peptides with delta opioid antagonist activity lacking Phe, considered essential for opioid activity based on the N-terminal tripeptide sequence (Tyr-D-Xaa-Phe) of amphibian skin opioids. Analogs were then designed to restrain the rotational flexibility of Tyr by the substitution of 2,6-dimethyl-L-tyrosine (Dmt).

Materials And Methods: Tyr and Dmt peptides were synthesized by solid phase and solution methods using Fmoc technology or condensing Boc-Dmt-OH or Boc-Tyr(But)-OH with H-L-Tic-OBut or H-D-Tic-OBut, respectively. Peptides were purified (> 99%) by HPLC and characteristics determined by 1H-NMR, FAB-MS, melting point, TLC, and amino acid analyses.

Results: H-Dmt-Tic-OH had high affinity (Ki delta = 0.022 nM) and extraordinary selectivity (Ki mu/Ki delta = 150,000); H-Dmt-Tic-Ala-OH had a Ki delta = 0.29 nM and delta selectivity = 20,000. Affinity and selectivity increased 8700- and 1000-fold relative to H-Tyr-Tic-OH, respectively. H-Dmt-Tic-OH and H-Dmt-Tic-NH2 fitted one-site receptor binding models (eta = 0.939-0.987), while H-Dmt-Tic-ol, H-Dmt-Tic-Ala-OH and H-Dmt-Tic-Ala-NH2 best fitted two-site models (eta = 0.708-0.801, F 18.9-26.0, p < 0.0001). Amidation increased mu affinity by 10- to 100-fold and acted synergistically with D-Tic2 to reverse selectivity (delta-->mu). Dmt-Tic di- and tripeptides exhibited delta antagonist bioactivity (Ke = 4-66 nM) with mouse vas deferens and lacked agonist mu activity (> 10 microM) in guinea-pig ileum preparations. Dmt-Tic analogs weakly interacted with kappa receptors in the 1 to > 20 microM range.

Conclusions: Dmt-Tic opioidmimetic peptides represent a highly potent class of opioid peptide antagonists with greater potency than the nonopioid delta antagonist naltrindole and have potential application as clinical and therapeutic compounds.

Citing Articles

Chemical tools for the opioids.

Duque M, Vallavoju N, Woo C Mol Cell Neurosci. 2023; 125:103845.

PMID: 36948231 PMC: 10247539. DOI: 10.1016/j.mcn.2023.103845.

Peptidomimetics and Their Applications for Opioid Peptide Drug Discovery.

Lee Y Biomolecules. 2022; 12(9).

PMID: 36139079 PMC: 9496382. DOI: 10.3390/biom12091241.

Novel Dimethyltyrosine-Tetrahydroisoquinoline Peptidomimetics with Aromatic Tetrahydroisoquinoline Substitutions Show Kappa and Mu Opioid Receptor Agonism.

Montgomery D, Anand J, Griggs N, Fernandez T, Hartman J, Sanchez-Santiago A ACS Chem Neurosci. 2019; 10(8):3682-3689.

PMID: 31199621 PMC: 6726392. DOI: 10.1021/acschemneuro.9b00250.

Molecular Pharmacology of δ-Opioid Receptors.

Gendron L, Cahill C, Von Zastrow M, Schiller P, Pineyro G Pharmacol Rev. 2016; 68(3):631-700.

PMID: 27343248 PMC: 4931872. DOI: 10.1124/pr.114.008979.

Tumor Targeting and Pharmacokinetics of a Near-Infrared Fluorescent-Labeled δ-Opioid Receptor Antagonist Agent, Dmt-Tic-Cy5.

Huynh A, Estrella V, Stark V, Cohen A, Chen T, Casagni T Mol Pharm. 2015; 13(2):534-44.

PMID: 26713599 PMC: 4936951. DOI: 10.1021/acs.molpharmaceut.5b00760.

References

Schiller P, Nguyen T, Chung N, Lemieux C . Dermorphin analogues carrying an increased positive net charge in their "message" domain display extremely high mu opioid receptor selectivity. J Med Chem. 1989; 32(3):698-703. DOI: 10.1021/jm00123a035. View

Tancredi T, Salvadori S, Amodeo P, Picone D, Lazarus L, Bryant S . Conversion of enkephalin and dermorphin into delta-selective opioid antagonists by single-residue substitution. Eur J Biochem. 1994; 224(1):241-7. DOI: 10.1111/j.1432-1033.1994.tb20017.x. View

Portoghese P . Bivalent ligands and the message-address concept in the design of selective opioid receptor antagonists. Trends Pharmacol Sci. 1989; 10(6):230-5. DOI: 10.1016/0165-6147(89)90267-8. View

Sagan S, Amiche M, Delfour A, Camus A, Mor A, Nicolas P . Differential contribution of C-terminal regions of dermorphin and dermenkephalin to opioid-sites selection and binding potency. Biochem Biophys Res Commun. 1989; 163(2):726-32. DOI: 10.1016/0006-291x(89)92283-3. View

Sagan S, Amiche M, Delfour A, Mor A, Camus A, Nicolas P . Molecular determinants of receptor affinity and selectivity of the natural delta-opioid agonist, dermenkephalin. J Biol Chem. 1989; 264(29):17100-6. View

Balboni G, Marastoni M, Picone D, Salvadori S, Tancredi T, Temussi P . New features of the delta opioid receptor: conformational properties of deltorphin I analogues. Biochem Biophys Res Commun. 1990; 169(2):617-22. DOI: 10.1016/0006-291x(90)90375-w. View

Lazarus L, Salvadori S, Santagada V, Tomatis R, Wilson W . Function of negative charge in the "address domain" of deltorphins. J Med Chem. 1991; 34(4):1350-5. DOI: 10.1021/jm00108a017. View

Lazarus L, Salvadori S, Tomatis R, Wilson W . Opioid receptor selectivity reversal in deltorphin tetrapeptide analogues. Biochem Biophys Res Commun. 1991; 178(1):110-5. DOI: 10.1016/0006-291x(91)91786-c. View

MELCHIORRI P, Negri L, Severini C, Corsi R, Soaje M, ERSPAMER V . Structure-activity relationships of the delta-opioid-selective agonists, deltorphins. Eur J Pharmacol. 1991; 195(2):201-7. DOI: 10.1016/0014-2999(91)90536-y. View

10.

Schiller P, Weltrowska G, Nguyen T, Lemieux C, Chung N, Marsden B . Conformational restriction of the phenylalanine residue in a cyclic opioid peptide analogue: effects on receptor selectivity and stereospecificity. J Med Chem. 1991; 34(10):3125-32. DOI: 10.1021/jm00114a023. View

11.

Charpentier S, Sagan S, Delfour A, Nicolas P . Dermenkephalin and deltorphin I reveal similarities within ligand-binding domains of mu- and delta-opioid receptors and an additional address subsite on the delta-receptor. Biochem Biophys Res Commun. 1991; 179(3):1161-8. DOI: 10.1016/0006-291x(91)91693-7. View

12.

Chandrakumar N, Yonan P, Stapelfeld A, Savage M, Rorbacher E, Contreras P . Preparation and opioid activity of analogues of the analgesic dipeptide 2,6-dimethyl-L-tyrosyl-N-(3-phenylpropyl)-D-alaninamide. J Med Chem. 1992; 35(2):223-33. DOI: 10.1021/jm00080a005. View

13.

Collin E, Cesselin F . Neurobiological mechanisms of opioid tolerance and dependence. Clin Neuropharmacol. 1991; 14(6):465-88. DOI: 10.1097/00002826-199112000-00001. View

14.

Hansen Jr D, Stapelfeld A, Savage M, Reichman M, Hammond D, Haaseth R . Systemic analgesic activity and delta-opioid selectivity in [2,6-dimethyl-Tyr1,D-Pen2,D-Pen5]enkephalin. J Med Chem. 1992; 35(4):684-7. DOI: 10.1021/jm00082a008. View

15.

Lazarus L, Salvadori S, Balboni G, Tomatis R, Wilson W . Stereospecificity of amino acid side chains in deltorphin defines binding to opioid receptors. J Med Chem. 1992; 35(7):1222-7. DOI: 10.1021/jm00085a009. View

16.

Marastoni M, Tomatis R, Balboni G, Salvadori S, Lazarus L . On the degradation of the deltorphin peptides by plasma and brain homogenate. Farmaco. 1991; 46(11):1273-9. View

17.

TAKEMORI A, Sultana M, Nagase H, Portoghese P . Agonist and antagonist activities of ligands derived from naltrexone and oxymorphone. Life Sci. 1992; 50(20):1491-5. DOI: 10.1016/0024-3205(92)90138-f. View

18.

Portoghese P . Edward E. Smissman-Bristol-Myers Squibb Award Address. The role of concepts in structure-activity relationship studies of opioid ligands. J Med Chem. 1992; 35(11):1927-37. DOI: 10.1021/jm00089a001. View

19.

ERSPAMER V . The opioid peptides of the amphibian skin. Int J Dev Neurosci. 1992; 10(1):3-30. DOI: 10.1016/0736-5748(92)90003-i. View

20.

Amodeo P, Motta A, Tancredi T, Salvadori S, Tomatis R, Picone D . Solution structure of deltorphin I at 265 K: a quantitative NMR study. Pept Res. 1992; 5(1):48-55. View