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Open AccessArticle

The Meta-Position of Phe4 in Leu-Enkephalin Regulates Potency, Selectivity, Functional Activity, and Signaling Bias at the Delta and Mu Opioid Receptors

1
Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, IN 47907, USA
2
Department of Medicinal Chemistry, The University of Kansas, Lawrence, KS 66045, USA
3
Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA
4
College of Wuya, Shenyang Pharmaceutical University, Shenyang 110016, China
5
Purdue Institute for Drug Discovery, Purdue University, West Lafayette, IN 47907, USA
6
Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, IN 47907, USA
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editors: Mariana Spetea and Helmut Schmidhammer
Molecules 2019, 24(24), 4542; https://doi.org/10.3390/molecules24244542
Received: 20 November 2019 / Revised: 8 December 2019 / Accepted: 10 December 2019 / Published: 12 December 2019
As tool compounds to study cardiac ischemia, the endogenous δ-opioid receptors (δOR) 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 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 Phe4 position of Leu5-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 Phe4 of Leu5-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 Phe4 may be combined with other modifications to Leu5-enkephalin to deliver improved agonists with finely tuned potency, selectivity, bias and drug-like properties. View Full-Text
Keywords: Leu-enkephalin; beta-arrestin; mu opioid receptor; delta opioid receptor; biased signaling; DADLE; ischemia; plasma stability Leu-enkephalin; beta-arrestin; mu opioid receptor; delta opioid receptor; biased signaling; DADLE; ischemia; plasma stability
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MDPI and ACS Style

Cassell, R.J.; Sharma, K.K.; Su, H.; Cummins, B.R.; Cui, H.; Mores, K.L.; Blaine, A.T.; Altman, R.A.; van Rijn, R.M. The Meta-Position of Phe4 in Leu-Enkephalin Regulates Potency, Selectivity, Functional Activity, and Signaling Bias at the Delta and Mu Opioid Receptors. Molecules 2019, 24, 4542.

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