Binding, pharmacological and immunological profiles of the delta-selectiveopioid receptor antagonist HS 378

HS 378 is a recently developed indolomorphinan with high selectivity and an tagonist potency at the delta -opioid receptor. The present study was perfo rmed 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 bra in homogenates. HS 378 showed 4.7- and 2.4- fold higher mu/delta selectivit y compared to NTI and NTB, respectively. In the [S-35]GTP gammaS functional assay carried out in cell lines expressing cloned human opioid receptors, FIS 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 con canavalin A induced rat T-lymphocyte proliferation with an IC50 value of 0. 54 muM. NTI showed also immunosuppression with an IC50 value of 6.93 muM wh ereas 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 fin dings indicate that the small molecule HS 378 has properties that may be of therapeutic value in the setting of human inflammatory diseases. (C) 2001 Elsevier Science Inc. All rights reserved.