Synthesis and pharmacology of halogenated δ-opioid-selective [D-Ala2]deltorphin II peptide analogues Journal Article
| Authors: | Pescatore, R.; Marrone, G. F.; Sedberry, S.; Vinton, D.; Finkelstein, N.; Katlowitz, Y. E.; Pasternak, G. W.; Wilson, K. R.; Majumdar, S. |
| Article Title: | Synthesis and pharmacology of halogenated δ-opioid-selective [D-Ala2]deltorphin II peptide analogues |
| 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-NH<inf>2</inf> 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 -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 K<inf>D</inf> 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 -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. © 2015 American Chemical Society. |
| Keywords: | controlled study; unclassified drug; dose response; nonhuman; binding affinity; animal cell; mouse; mus; animal experiment; animal model; in vitro study; drug synthesis; anura; iodine 125; analgesia; mu opiate receptor; peptide synthesis; analgesic agent; enkephalin[2,5 dextro penicillamine]; naltrindole; analgesic activity; cricetulus griseus; delta opiate receptor; deltorphin; binding assay; kappa opiate receptor; radioiodination; sandmeyer reaction; male; priority journal; article; delta opioid receptor; sandmeyer; delta opiate receptor agonist; gate3 8 peptide; phyllomedusa bicolor |
| Journal Title: | ACS Chemical Neuroscience |
| Volume: | 6 |
| Issue: | 6 |
| ISSN: | 1948-7193 |
| Publisher: | American Chemical Society |
| Date Published: | 2015-06-17 |
| Start Page: | 905 |
| End Page: | 910 |
| Language: | English |
| DOI: | 10.1021/acschemneuro.5b00060 |
| PROVIDER: | scopus |
| PMCID: | PMC4472604 |
| PUBMED: | 25844930 |
| DOI/URL: | |
| Notes: | Export Date: 3 August 2015 -- Source: Scopus |
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