SYSTEMATIC STRUCTURE-ACTIVITY RELATIONSHIP STUDIES OF NALFURAFINE

Today’s opioid crisis is one of the most challenging public health emergency. Two million Americans suffer opioid addiction. Over 20 million adults are affected by daily pain without non-addictive analgesics. Kappa opioid receptor (KOR) is one of the most studied new pain targets void of abuse liability. KOR agonists have shown potent analgesia and also potential in alleviating opioid addiction. The only approved KOR agonist in clinic is nalfurafine (NFU). Though not leading to addiction, the analgesic effects of NFU are accompanied by sedative side effects. Therefore, we designed a systematical structure-activity relationship study of NFU for developing non-addictive analgesics. Stereoselective strategies and time-efficient “one-pot” methods were designed and conducted for synthesizing eight essential intermediates. Then the designed final compounds (K1-K8) were prepared and characterized in binding and functional assays, i.e. radioligand binding assays, [35S]GTPgS binding assay, and calcium assay. Seven compounds possessed subnanomolar binding affinities towards KOR. All compounds demonstrated dual KOR-DOR agonism and low efficacy at MOR. SAR conclusions were drawn to guide future studies. In the following tail-flick assays, six compounds exhibited potent analgesia, four of which had higher potencies than morphine. The most potent compound, K3, was 63-fold more potent than morphine. Because K3 is not only a potent KOR agonist but also a potent DOR agonist. We hypothesized that K3 is less likely to cause sedation while achieving potent analgesia. Therefore, K3 was identified as a new hit and will be verified for its non-abusing and non-sedating features in due course