- Peptide and Peptidomimetic Drug Design
- Peptide Structure-Function
- Topographical Considerations in Molecular Recognition
- Organic, Amino Acid and Peptide Synthesis
- Pain mechanisms and Drug Abuse
There are very few treatments for chronic neuropathic pain and those that are available are often ineffective, have numerous toxicities, and can lead to dependence, addiction, and low quality of life. The goal of my research is to develop new class of ligands for the treatment of chronic neuropathic pain that represents design, synthesis, and biological evaluation.
Our early studies in drug discovery for the treatment of chronic pain represented a new approach: drug design for pathological conditions and multifunctional ligands. Drug design based on normal pain states is inadequate due to adaptation and neuroplasticity. Adaptations to this condition include upregulated endogenous neurotransmitters such as cholecystokinin, which stimulates pronociceptive effects and is anti-opioid. The development of multifunctional ligands and systems-based drug design offers a critical new approach to efficacy for chronic pain states. This brand new approach is in need of new ideas and new paradigms.
Chronic pain, nerve injury and inflammation often result in the up regulation of Dynorphin A in the spinal column neurotransmitter pathway to the brain. Our studies have discovered a novel mechanism of neurotransmission related to pain in which the bradykinin receptors are upregulated and Dynorphin A peptides have neuroexcitatory effects that result in hyperalgesia. Our studies have also shown that lead ligand LYS1044 blocks Dyn A-induced hyperalgesia and motor impairments in naïve animals and inhibits thermal hyperalgesia and mechanical hypersensitivity in a dose-dependent manner in nerve-injured animals. Importantly, the ability of LYS1044 is limited to the CNS and thus can avoid serious cardiovascular effects caused by blocking peripheral bradykinin receptors. This study presents a new class of ligands based on the unanticipated pathophysiological interaction between the endogenous opioid ligand dynorphin A and bradykinin receptors for the treatment of chronic pain without the toxicities associated with current treatments for these maladies.
Opioid peptides are limited as clinically viable drugs due to poor bioavailability, mainly due to low BBB penetration. The modulation of mu and delta opioid receptors is known to provide higher efficacy, lower mu opioid dose requirements, and consequent increased safety from synergistic effects. Therefore, nonselective bifunctional ligands possessing mu and delta opioid receptor agonist activities for synergistic effects and high lipophilicity for improved BBB penetration are significant. A series of highly lipophilic enkephalin analogues with the C-terminal modification exhibited very potent analgesic effects in vivo with high lipophilicity indicates the concurrent improvements of potency and bioavailability. Recent discovery that enkephalin analogue developed for mu and delta opioid receptor agonist activity, also interacts with kappa opioid receptor as an antagonist opens up the possibility of developing novel opioid drugs with clear therapeutic advantages for the treatment of chronic pain. This represents a new biological profile to be effective analgesics with reduced undesirable adverse qualities, since chronic pain up-regulates KOR, diminishing the analgesic effectiveness of MOR agonists, causing stress, anxiety, and depression, and potentially enhancing addictive liability. Our study will identify key structural features of enkephalin for the KOR antagonist activity and provide a new strategy to build a highly integrated structure for three opioid receptors using a short peptide like enkephalin