Evaluation of samidorphan, a μ-opioid antagonist, in a drug discrimination assay in rats

: Preclinical Research & Development Background: Samidorphan, a μ-opioid receptor antagonist, is in clinical development for central nervous system related diseases. The discriminative stimulus effects of samidorphan were assessed in rats trained to discriminate the effects of a known morphinan of abuse, morphine, from that of saline. METHODS: Escalating doses of samidorphan were substituted for morphine and rats were allowed to respond on two levers for food reward. Doses of samidorphan were chosen based on other pharmacodynamic assays in which samidorphan blocked the effects of morphine (such as blocking analgesia in a hot plate test; data not shown). In addition, a pharmacokinetic study was conducted to determine if these doses would reflect predicted exposure levels that translate to human equivalent doses. RESULTS: Rats discriminating morphine from vehicle responded predominantly on the vehicle lever after receiving samidorphan. In addition, samidorphan was rapidly absorbed, and plasma concentrations of the doses tested in this study bracket therapeutically relevant concentrations. CONCLUSIONS: In summary, samidorphan produced saline-like behavioral responses over a wide dose range.