The pharmacological treatment of pain has long been limited by the negative side effects of opioids: development of tolerance, dependence, and danger of overdose. A literature has developed linking opiate side effects to their influence on glial cells within the central nervous system (CNS). These effects have been shown to result from toll-like receptor 4 (TLR4)-mediated glial activation, which causes both pain enhancement and opioid tolerance and dependence. As such, there is an urgent need to understand opioid dysregulation via TLR4. The objective of this current proposal is to optimize a small-molecule probe identified from virtual screening, which in turn will be used to study glial activation and its impact on opioid effectiveness. The rationale underlying this research is that optimized small molecule TLR4 inhibitors can serve as highly specific probes to study the molecular mechanism of opioid-induced glial activation. The proposed research is significant because the optimized small molecule agents will preclude the development of novel therapeutics to increase opiate efficacy and safety. The proposed research is innovative because it is the first drug discovery approach attempting to regulate opioid-induced glial activation. The studies are built on a strong collaborative team with expertise that optimizes its chance to effectively bridge the atomic detail of TLR4 activation with the macroscopic pain management inefficiencies of opioid use.
In Aim 1, extensive structure-activity relationship studies will be carried out to optimize the lead compound indentified from in silico screening. Established in vitro biophysical and cellular assays will then be used to evaluate synthesized small molecule agents for their potency in blocking TLR4 activation. Crystallization of TLR4 in complex with the small-molecule ligands will be attempted in a parallel effort to elucidate the structural geometry of TLR4 inhibition. These results will shed light on the molecular recognition in the ligand/receptor association, thereby providing insights for the optimization of the first generation small molecule inhibitors.
Aim 2 will test the second working hypothesis, that by inhibiting opioid-induced TLR4 activation, glial activation can also be blocked, thus enhancing analgesia as well as reduce tolerance and dependence on opioids. The proposed studies, if successful, are projected to yield significant novel outcome: First, the results will shed light on the mechanism of clinically relevant opioid-induced glial activation. Second, the small molecule antagonists of TLR4 identified from the proposed research will serve as prototypes for potential drug candidates. These inhibitors may be clinically useful in the treatment of opioid side effects, addressing a public heath issue that encompasses opioid addiction, tolerance, and abusing.
The proposed research aims to unravel the mechanism of opioid-induced glial activation that both hinders the ability of opioids to effectively control pain and also importantly contributes to the development of drug addiction and abuse. State-of-the-art technologies will be employed to define, design, create, and test new chemical entities predicted to prevent opioid induced glial activation, thereby optimizing opioid analgesia while preventing negative consequences of clinical opioid use.
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