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Volume 7
Journal of Pain & Relief
ISSN: 2167-0846
Pain Management 2018
October 11-12, 2018
Page 41
conference
series
.com
October 11-12, 2018 | Zurich, Switzerland
7
th
International Conference and Exhibition on
Pain Research and Management
Peter W. Schiller, J Pain Relief 2018, Volume 7
DOI: 10.4172/2167-0846-C1-019
Bi- or multifunctional opioid analgesics
A
cute 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 painmodel and in one case
did not produce respiratory depression.
Recent Publications
1. Schiller PW, Nguyen TM-D, Saray A, Poon AWH, Laferrière A and Coderre T J (2015) The bifunctional µ opioid agonist/
antioxidant [Dmt1]DALDA is a superior analgesic in an animal model of complex regional pain syndrome-type 1. ACS
Chemical Neuroscience 6:1789-1793.
2. Toyama S, Shimoyama N, Szeto H H, Schiller P W and Shimoyama M (2018) Protective effect of a mitochondria-targeted
peptide against the development of chemotherapy-induced peripheral neuropathy in mice. ACS Chemical Neuroscience
DOI: 10.1021/acschemneuro.8b00013.
3. Ballet S, Betti C, Novoa A, Tömböly C, Nielsen C U, Helms H C, Lesniak A, Kleczkowska P, Chung N N, Lipkowski A
W, Brodin B, Tourwé D and Schiller W (2014)
In vitro
membrane permeation studies and
in vivo
antinociception of
glycosylated Dmt1-DALDA analogues. ACS Medicinal Chemistry Letters 5:352-357.
4. Betti C, Mika J, Dyniewicz J, Frankiewicz L, Novoa A, Keresztes A, Kosson P, Van Duppen J, Chung N N, Vandenbroeck J,
Lipkowski A W, Schiller P W, Przewlocka B, Tourwé D and Ballet S (2015) Dual alleviation of acute and neuropathic pain
by fused opioid agonist-neurokinin 1 antagonist peptidomimetics. ACS Medicinal Chemistry Letters 6:1209-1214.
5. Guillemyn K, Starnowska J, Lagard C, Dyniewicz J, Chung NN, Kosson P, Lipkowski A W, Chevillard L, Megarbane B,
Tourwé D, Simonin F, Przewlocka B, Schiller P W and Ballet S (2016) Bifunctional and peptide-based opioid agonist-
nociceptin antagonist ligands for dual treatment of acute and neuropathic pain. Journal of Medicinal Chemistry 59:3777-
3792.
Peter W. Schiller
Montreal Clinical Research Institute, Canada
University of Montreal, Canada