Biography
Biography: Peter W. Schiller
Abstract
Acute pain typically responds well to treatment with opioids and NSAIDs, whereas neuropathic pain is difficult to treat with only 40-60% of patients achieving pain relief. Currently used treatments, including tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors, anticonvulsants and morphine are either ineffective or produce major, limiting side effects. Our goal is to develop opioids with novel bi- or multifunctional activity profiles for treatment of chronic pain with minimal side effects. [Dmt1]DALDA (SS-02), a tetrapeptide with excellent drug-like properties, is a potent mu opioid analgesic and also is a mitochondria-targeted antioxidant. Mitochondrial reactive oxygen species (ROS) play a key role in mechanisms of neuropathic pain and there is evidence that ROS quenchers synergize with opiates in alleviating neuropathic pain. As expected, SS-02 turned out to be more effective than morphine in a rat model of neuropathic pain. Similarly, in a rat model of complex regional pain syndrome (CRPS-1), SS-02 and one of its analogues produced an up to 70-fold more potent and longer-lasting analgesic effect as compared to morphine. A structurally related peptide (SS-20) capable of promoting mitochondrial energetics had a protective effect against the development of chemotherapy-induced peripheral neuropathy in mice. Thus, these compounds are excellent drug candidates for neuropathic pain treatment. In a different approach we developed bifunctional compounds that target two distinct receptors. On the basis of a strong pharmacological rationale compounds were designed that act as agonists at the mu opioid receptor (MOR) and as antagonists at the delta opioid receptor (DOR). Such MOR agonist/DOR antagonists turned out to be potent analgesics in the rat tail flick test with low propensity to produce analgesic tolerance and dependence. Furthermore, bifunctional MOR agonist/NK1 receptor antagonists and opioid agonist/nociceptin antagonists were more potent than morphine in a neuropathic pain model and in one case did not produce respiratory depression.