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The Meta-Position of Phe4 in Leu-enkephalin Regulates Potency, Selectivity, Functional Activity, and Signaling Bias at the Delta and Mu Opioid Receptors
The Meta-Position of Phe4 in Leu-enkephalin Regulates Potency, Selectivity, Functional Activity, and Signaling Bias at the Delta and Mu Opioid Receptors
- Source :
- Molecules, Volume 24, Issue 24
- Publication Year :
- 2019
- Publisher :
- Cold Spring Harbor Laboratory, 2019.
-
Abstract
- As tool compounds to study cardiac ischemia, the endogenous &delta<br />opioid receptors (&delta<br />OR) agonist Leu5-enkephalin and the more metabolically stable synthetic peptide (d-Ala2, d-Leu5)-enkephalin are frequently employed. However, both peptides have similar pharmacological profiles that restrict detailed investigation of the cellular mechanism of the &delta<br />OR&rsquo<br />s protective role during ischemic events. Thus, a need remains for &delta<br />OR peptides with improved selectivity and unique signaling properties for investigating the specific roles for &delta<br />OR signaling in cardiac ischemia. To this end, we explored substitution at the Phe4 position of Leu5-enkephalin for its ability to modulate receptor function and selectivity. Peptides were assessed for their affinity to bind to &delta<br />ORs and &micro<br />opioid receptors (&micro<br />ORs) and potency to inhibit cAMP signaling and to recruit &beta<br />arrestin 2. Additionally, peptide stability was measured in rat plasma. Substitution of the meta-position of Phe4 of Leu5-enkephalin provided high-affinity ligands with varying levels of selectivity and bias at both the &delta<br />OR and &micro<br />OR 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 Phe4 may be combined with other modifications to Leu5-enkephalin to deliver improved agonists with finely tuned potency, selectivity, bias and drug-like properties.
- Subjects :
- Agonist
medicine.drug_class
G protein
DADLE
Pharmaceutical Science
Endogeny
Peptide
ischemia
mu opioid receptor
Analytical Chemistry
δ-opioid receptor
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Drug Discovery
medicine
cardiovascular diseases
plasma stability
Physical and Theoretical Chemistry
Receptor
030304 developmental biology
Leu-enkephalin
biased signaling
chemistry.chemical_classification
0303 health sciences
beta-arrestin
Organic Chemistry
3. Good health
chemistry
Chemistry (miscellaneous)
delta opioid receptor
Biophysics
cardiovascular system
Molecular Medicine
μ-opioid receptor
Selectivity
030217 neurology & neurosurgery
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Molecules, Volume 24, Issue 24
- Accession number :
- edsair.doi.dedup.....addc6d89cd13daf29de127a199d1e068
- Full Text :
- https://doi.org/10.1101/750794