G protein independent phosphorylation and internalization of the delta-opioid receptor.

Agonist activation of the delta-opioid receptor leads to internalization via G betagamma recruitment of G protein coupled receptor kinase-2, which phosphorylates the receptor at several sites, including Ser363, allowing beta-arrestin binding and localization to clathrin coated pits. Using human embryonic kidney cells expressing a delta-opioid receptor we tested the hypothesis that prevention of receptor coupling to G protein by treatment with pertussis toxin (PTX) will block these processes. PTX treatment did not reduce phosphorylation of delta-opioid receptor Ser363 in response to the agonist [D-Pen2, D-Pen5]enkephalin, or recruitment of beta-arrestin 2-green fluorescent protein to the membrane and only slowed, but did not prevent, [D-Pen2, D-Pen5]enkephalin-induced internalization.

Mixed kappa/mu opioid receptor agonists: the 6 beta-naltrexamines.

Ligands from the naltrexamine series have consistently demonstrated agonist activity at kappa opioid receptors (KOR), with varying activity at the mu opioid receptor (MOR). Various 6 beta-cinnamoylamino derivatives were made with the aim of generating ligands with a KOR agonist/MOR partial agonist profile, as ligands with this activity may be of interest as treatment agents for cocaine abuse. The ligands all displayed the desired high affinity, nonselective binding in vitro and in the functional assays were high efficacy KOR agonists with some partial agonist activity at MOR.