BBB Major Publications

Document Type

Journal Article

Date of this Version

4-2015

Publication Source

ACS Chemical Neuroscience

Volume

6

Issue

6

Start Page

905

Last Page

910

DOI

10.1021/la4047758

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-Ala2]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 [35S]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 125I 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 Phe3. 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.

Copyright/Permission Statement

This is a pre-publication version accepted for publication in ACS Chemical Neuroscience by the American Chemical Society ©2015. Reproduced with permission. Do not copy or disclose without written permission from the American Chemical Society.

Comments

At the time of this publication, Dr. Katlowitz was affiliated with the Memorial Sloan-Kettering Cancer Center, but Dr. Katlowitz is now affiliated with the Children's Hospital of Philadelphia (CHOP).

Keywords

delta opiod receptor, deltorphin, radioiodination, sandmeyer

 

Date Posted:18 July 2017

This document has been peer reviewed.