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THU0013 Biological and immunological profiles of the delta-selective opioid receptor antagonist hs 378
  1. M Spetea1,
  2. H Erlandsson-Harris2,
  3. I Berzetei-Gurske3,
  4. L Klareskog2,
  5. H Schmidhammer1
  1. 1Department of Pharmacy, University of Innsbruck, Innsbruck, Austria
  2. 2Department of Rheumatology, Karolinska Institute, Stockholm, Sweden
  3. 3Pharmaceutical Division, SRI International, Menlo Park, CA, USA

Abstract

Background Immuno-hyperreactivity is a fundamental process in inflammatory conditions such as rheumatoid arthritis. Delta-selective opioid receptor antagonists have been shown to exhibit inhibitory effects on inflammation. Therefore, the development of such compounds is highly promising with regard to selective action and is also of potential clinical relevance for human inflammatory diseases. HS 378 is a recently developed indolomorphinan with high selectivity and antagonist potency at the delta-opioid receptor.

Objectives The present study was performed to characterise 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 and naltriben.

Methods In vitro opioid receptor binding profiles were determined in rat brain homogenates. Agonist/antagonist potency of HS 378 was determined in the [35S]GTPγS functional assay using membranes from CHO cells transfected with cloned human opioid receptors. In order to assess immunological activity, HS 378 was tested on concanavaline a stimulated rat T-lymphocytes.

Results HS 378 showed 4.7- and 2.4-fold higher mu/delta selectivity compared to naltrindole and naltriben, respectively. In the [35S]GTPγS functional assay, HS 378 resulted in an apparent dose-related suppression of concanavaline A induced rat T-lymphocyte proliferation with an IC50 value of 0.54 μM. The IC50 of HS 378 was 13 times lower than that of naltrindole and 8 times higher than that of cyclosporine A.

Conclusion 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.

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