oripavine and 18-19-dihydroetorphine

This study examines the possibility that oripavine opioid receptor agonists bind equally to both high and low affinity states of the mu-opioid receptor. Studies were performed in C6 cells expressing mu- or delta-opioid receptors; high and low agonist affinity states of the receptors were defined by the absence and presence, respectively of Na+ ions and the GTP analog Gpp(NH)p. At the mu-opioid receptor dihydroetorphine and etorphine were full agonists, buprenorphine had moderate efficacy while diprenorphine was an antagonist. At the delta-opioid receptor, dihydroetorphine, etorphine, and diprenorphine had moderate efficacy while buprenorphine was an antagonist. The binding affinities of the oripavines at the mu-opioid receptor decreased only one to 2-fold in the presence of NaCl and Gpp(NH)p. In contrast, decreases in oripavine affinity at the delta-opioid receptor correlated with delta-opioid receptor efficacy. The ability of oripavine agonists to bind with high affinity to the low agonist affinity state of the nu-opioid receptor may explain the high potencies of these compounds in vivo.

Topics: Analgesics, Opioid; Animals; Benzamides; Binding, Competitive; Buprenorphine; Cloning, Molecular; Diprenorphine; Dose-Response Relationship, Drug; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Etorphine; Fentanyl; Guanosine 5'-O-(3-Thiotriphosphate); Morphine; Naloxone; Piperazines; Radioligand Assay; Rats; Receptors, Opioid, delta; Receptors, Opioid, mu; Sulfur Radioisotopes; Thebaine; Tritium; Tumor Cells, Cultured

The present study was undertaken to compare the neurotoxic effects of three etorphine-like opiates (etorphine, dihydroetorphine, and another derivative of oripavine) and heroin with their ability to activate opiate receptors in human neuroblastoma cell line SK-N-SH as well as in two other neuronal cell lines. Neurotoxicity was measured by using [3H]-thymidine incorporation analysis, cell viability measurement and Cytosensor microphysiometry. It was found that, in spite of the very similar molecular structures of these opiates, they displayed significant differences in cytotoxicity, with etorphine and another derivative of oripavine possessing high potency but dihydroetorphine and heroin little effect. However, neurotoxic potency of the opiates was not directly correlated to their ability to activate opioid receptors, as determined by [35S]-guanylyl-5'-O-(gamma-tho)-triphosphate binding assay. These findings provide clear evidence of differential neurotoxicity of etorphine-like opiates, and suggest that the neurotoxicity is not closely related to the molecular configuration required as opioid receptor agonist but is probably associated with the presence of a double bond in the structure.

Topics: Animals; Cell Survival; Etorphine; Guanosine 5'-O-(3-Thiotriphosphate); Heroin; Humans; Narcotics; Neuroblastoma; Neurotoxins; PC12 Cells; Rats; Receptors, Opioid; Structure-Activity Relationship; Thebaine; Tumor Cells, Cultured