Pescatore, RobynMarrone, Gina FSedberry, SethVinton, DanielFinkelstein, NetanelKatlowitz, Yitzchak EPasternak, Gavril WWilson, Krista RMajumdar, Susruta2023-05-222023-05-222015-04-012017-07-18https://repository.upenn.edu/handle/20.500.14332/2750Deltorphins 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.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.delta opiod receptordeltorphinradioiodinationsandmeyerChemicals and DrugsNeurologyNeuroscience and NeurobiologyNeurosciencesArticle