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

ABSTRACT: Deltorphins are naturally occurring peptides produced by the skin of the giant monkey frog (Phyllomedusa bicolor). They are ?-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 ?-selective in in vitro radioligand binding assays over the ?- and ?-opioid receptors. It is a full agonist in [(35)S]GTP?S functional assays and analgesic when administered supraspinally to mice. Analgesia of 3 (GATE3-8) is blocked by the selective ? receptor antagonist naltrindole, indicating that the analgesic action of 3 is mediated by the ?-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 ? 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 ?-, ?-, 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 ?-opioid receptor pharmacology.

SUBMITTER: Pescatore R 

PROVIDER: S-EPMC4472604 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature