» Articles » PMID: 31842282

The Meta-Position of Phe in Leu-Enkephalin Regulates Potency, Selectivity, Functional Activity, and Signaling Bias at the Delta and Mu Opioid Receptors

Overview
Journal Molecules
Publisher MDPI
Specialty Biology
Date 2019 Dec 18
PMID 31842282
Citations 9
Authors
Affiliations
Soon will be listed here.
Abstract

As tool compounds to study cardiac ischemia, the endogenous δ-opioid receptors (δOR) agonist Leu-enkephalin and the more metabolically stable synthetic peptide (d-Ala, d-Leu)-enkephalin are frequently employed. However, both peptides have similar pharmacological profiles that restrict detailed investigation of the cellular mechanism of the δOR's protective role during ischemic events. Thus, a need remains for δOR peptides with improved selectivity and unique signaling properties for investigating the specific roles for δOR signaling in cardiac ischemia. To this end, we explored substitution at the Phe position of Leu-enkephalin for its ability to modulate receptor function and selectivity. Peptides were assessed for their affinity to bind to δORs and µ-opioid receptors (µORs) and potency to inhibit cAMP signaling and to recruit β-arrestin 2. Additionally, peptide stability was measured in rat plasma. Substitution of the meta-position of Phe of Leu-enkephalin provided high-affinity ligands with varying levels of selectivity and bias at both the δOR and µOR and improved peptide stability, while substitution with picoline derivatives produced lower-affinity ligands with G protein biases at both receptors. Overall, these favorable substitutions at the meta-position of Phe may be combined with other modifications to Leu-enkephalin to deliver improved agonists with finely tuned potency, selectivity, bias and drug-like properties.

Citing Articles

Efficacy of dual enkephalinase inhibition in a preclinical migraine model is mediated by activation of peripheral delta opioid receptors.

Mei H, Hu Y, Kapadia S, Ouimet T, Poras H, Dussor G Headache. 2023; 63(5):621-633.

PMID: 37183526 PMC: 10646790. DOI: 10.1111/head.14517.


Receptor expression and signaling properties in the brain, and structural ligand motifs that contribute to delta opioid receptor agonist-induced seizures.

Blaine A, van Rijn R Neuropharmacology. 2023; 232:109526.

PMID: 37004753 PMC: 11078570. DOI: 10.1016/j.neuropharm.2023.109526.


Population transcriptomics uncover the relative roles of positive selection and differential expression in Batrachium bungei adaptation to the Qinghai-Tibetan plateau.

Yu X, Wei P, Zhao S, Chen Z, Li X, Zhang W Plant Cell Rep. 2023; 42(5):879-893.

PMID: 36973418 DOI: 10.1007/s00299-023-03005-w.


Peptidomimetics and Their Applications for Opioid Peptide Drug Discovery.

Lee Y Biomolecules. 2022; 12(9).

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


Opportunities and Challenges for In Silico Drug Discovery at Delta Opioid Receptors.

Meqbil Y, van Rijn R Pharmaceuticals (Basel). 2022; 15(7).

PMID: 35890173 PMC: 9324648. DOI: 10.3390/ph15070873.


References
1.
Shenmar K, Sharma K, Wangoo N, Maurya I, Kumar V, Khan S . Synthesis, stability and mechanistic studies of potent anticryptococcal hexapeptides. Eur J Med Chem. 2017; 132:192-203. PMC: 5476684. DOI: 10.1016/j.ejmech.2017.03.046. View

2.
Rosa M, Caltabiano G, Barreto-Valer K, Gonzalez-Nunez V, Gomez-Tamayo J, Arda A . Modulation of the Interaction between a Peptide Ligand and a G Protein-Coupled Receptor by Halogen Atoms. ACS Med Chem Lett. 2015; 6(8):872-6. PMC: 4538429. DOI: 10.1021/acsmedchemlett.5b00126. View

3.
Sarin V, Kent S, Tam J, MERRIFIELD R . Quantitative monitoring of solid-phase peptide synthesis by the ninhydrin reaction. Anal Biochem. 1981; 117(1):147-57. DOI: 10.1016/0003-2697(81)90704-1. View

4.
Weinberger S, Martinez Jr J . Characterization of hydrolysis of [leu]enkephalin and D-ala2-[L-leu]enkephalin in rat plasma. J Pharmacol Exp Ther. 1988; 247(1):129-35. View

5.
Simantov R, Kuhar M, Pasternak G, Snyder S . The regional distribution of a morphine-like factors enkephalin in monkey brain. Brain Res. 1976; 106(1):189-97. DOI: 10.1016/0006-8993(76)90086-x. View