title: Binding, pharmacological and immunological profiles of the delta-selective opioid receptor antagonist HS 378.
abstract: HS 378 is a recently developed indolomorphinan with high selectivity and antagonist potency at the delta-opioid receptor. The present study was performed to characterize the opioid binding properties and pharmacological and immunological activity of HS 378 and to compare them with those of two well-known delta-opioid receptor antagonists, naltrindole (NTI) and naltriben (NTB). In vitro opioid receptor binding profiles were determined in rat brain homogenates. HS 378 showed 4.7- and 2.4-fold higher mu/delta selectivity compared to NTI and NTB, respectively. In the [35S]GTPgammaS functional assay carried out in cell lines expressing cloned human opioid receptors, HS 378 was found to be a pure delta-opioid receptor antagonist. In vitro, exposure of HS 378 resulted in an apparent dose-related suppression of concanavalin A induced rat T-lymphocyte proliferation with an IC50 value of 0.54 microM. NTI showed also immunosuppression with an IC50 value of 6.93 microM, whereas NTB had no effect. The IC50 of HS 378 was 13 times lower than that of NTI and 8 times higher than that of cyclosporin A. Taken together, our findings indicate that the small molecule HS 378 has properties that may be of therapeutic value in the setting of human inflammatory diseases.
authors.affiliation: Division of Pharmaceutical Chemistry, Institute of Pharmacy, University of Innsbruck, Austria. Mariana.Spetea@uibk.ac.at
authors.forename: M
authors.initials: M
authors.lastname: Spetea
authors.forename: H E
authors.initials: HE
authors.lastname: Harris
authors.forename: I P
authors.initials: IP
authors.lastname: Berzetei-Gurske
authors.forename: L
authors.initials: L
authors.lastname: Klareskog
authors.forename: H
authors.initials: H
authors.lastname: Schmidhammer
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D002478:Cells, Cultured; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000378:metabolism / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects*; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000378:metabolism* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
chemical_list: C437947:HS 378; D007166:Immunosuppressive Agents; D009292:Narcotic Antagonists; D017465:Receptors, Opioid, delta; C068868:naltrindole benzofuran; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D009271:Naltrexone; C055382:naltrindole