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ACS Chem Neurosci. 2015 Jun 17;6(6):905-10. doi: 10.1021/acschemneuro.5b00060. Epub 2015 Apr 14.

Synthesis and pharmacology of halogenated δ-opioid-selective [d-Ala(2)]deltorphin II peptide analogues.

Author information

1
†Department of Chemistry, Wingate University, PO Box 159, Wingate, North Carolina 28174, United States.
2
‡Department of Neuroscience, Weil Cornell Medical College, 1300 York Avenue, New York, New York 10065, United States.
3
§Department of Neurology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, United States.

Abstract

Deltorphins are naturally occurring peptides produced by the skin of the giant monkey frog (Phyllomedusa bicolor). They are δ-opioid receptor-selective agonists. Herein, we report the design and synthesis of a peptide, Tyr-d-Ala-(pI)Phe-Glu-Ile-Ile-Gly-NH2 3 (GATE3-8), based on the [d-Ala(2)]deltorphin II template, which is δ-selective in in vitro radioligand binding assays over the μ- and κ-opioid receptors. It is a full agonist in [(35)S]GTPγS functional assays and analgesic when administered supraspinally to mice. Analgesia of 3 (GATE3-8) is blocked by the selective δ receptor antagonist naltrindole, indicating that the analgesic action of 3 is mediated by the δ-opioid receptor. We have established a radioligand in which (125)I is incorporated into 3 (GATE3-8). The radioligand has a KD of 0.1 nM in Chinese hamster ovary (CHO) cells expressing the δ receptor. Additionally, a series of peptides based on 3 (GATE3-8) was synthesized by incorporating various halogens in the para position on the aromatic ring of Phe(3). The peptides were characterized for binding affinity at the μ-, δ-, and κ-opioid receptors, which showed a linear correlation between binding affinity and the size of the halogen substituent. These peptides may be interesting tools for probing δ-opioid receptor pharmacology.

KEYWORDS:

Deltorphin; delta opioid receptor; radioiodination; sandmeyer

PMID:
25844930
PMCID:
PMC4472604
DOI:
10.1021/acschemneuro.5b00060
[Indexed for MEDLINE]
Free PMC Article

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