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. Since 2000, I have been actively involved in the collaboration with Dr. Frank Porreca and Dr. Todd W. Vanderah in the Department of Pharmacology. Collaboration has improved not only the quality of research but also advances the field of pain and drug abuse treatments. This interaction resulted in the discovery of two novel ligands LYS739 and LYS1044.
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.
1. Cyf N. Ramos-Colon; Yeon Sun Lee; Michael Remesic; Sara M. Hall; Justin LaVigne; Peg Davis; Alexander J. Sandweiss; Mary I. McIntosh; Jessica Hanson; Tally M. Largent-Milnes; Todd W. Vanderah; John Streicher;, Frank Porreca; and Victor J. Hruby. “Structure Activity Relationships of [des-Arg7]- Dynorphin A Analogues at the Kappa Opioid Receptor” J. Med. Chem. 2016, 59(22), 10291-10298.
2. Yeon Sun Lee; Michael Remesic; Cyf Ramos-Colon; Sara M. Hall; Alexander Kuzmin; David Rankin; Frank Porreca; Josephine Lai; Victor J. Hruby “Cyclic non-opioid dynorphin A analogues for the bradykinin receptors” Bioorganic. Med. Chem. Lett. 2016, 26(22), 5513-5516.
3. Sara M. Hall; Lindsay LeBaron; Cyf Ramos-Colon; Chaoling Qu, Jennifer Yanhua Xie; Frank Porreca; Josephine Lai; Yeon Sun Lee; Victor J. Hruby. “Discovery of stable non-opioid dynorphin A analogues interacting at the bradykinin receptors for the treatment of neuropathic pain” ACS Chem. Neurosci. 2016, 7, 1746-1752.
4. Mohammad Rashedul Islam; Li Yang, Yeon Sun Lee; Victor J Hruby; Thomas J Abbruscato “Enkephalin-fentanyl multifunctional opioids as potential neuroprotectants for ischemic stroke treatment: Comparison to biphalin and fentanyl” Curr. Pharm. Des., 2016, 22(42), 6459-6468.
5. Yeon Sun Lee; Robert Kupp; Michael V. Remesic; Cyf Ramos-Colon; Sara M. Hall; David Rankin; Frank Porreca; Josephine Lai; Victor J. Hruby “Various modifications of the amphipathic dynorphin A phamacophore for rat brain bradykinin receptors” Chem. Bio. & Drug Des., 2016, 88, 615-619.
6. Scott M. Cowell; Yeon Sun Lee “Biphalin: the foundation of bivalent ligands” Curr. Med. Chem., 2016, 23(29), 3267-3284.
7. Michael Remesic; Yeon Sun Lee; Victor J. Hruby “Cyclic opioid peptides” Curr. Med. Chem., 2016, 23(13), 1288-1303. (Selected by the Editor-in-Chief as Editor’s choice to promote through a press release at EurekAlert platform, http://www.eurekalert.org/pub_releases/2016-07/bsp-cop071316.php)
8. Sara M. Hall; Yeon Sun Lee; Victor J. Hruby “Dynorphin A analogues for the treatment of chronic neuropathic pain” Fut. Med. Chem., 2016, 8, 165-177.
9. Dina V. Hingoran; Luis A. Montano; Edward A. Randtke; Yeon Sun Lee; Julio Cardenas Rodriguez; Mark D. Pagel “A single diamagnetic cataly CEST MRI contrast agent that detects cathepsin B enzyme activity by using a ratio of two CEST signals” Contrast Media Molec Imaging, 2016, 11(2), 130-138.
10. Yeon Sun Lee; Sara M. Hall; Cyf Ramos-Colon; Michael Remesic; David Rankin; Todd W. Vanderah; Frank Porreca; Josephine Lai; Victor J. Hruby “Blockade of non-opioid excitatory effects of spinal dynorphin A at bradykinin receptors” Receptors Clin Investig 2015, doi: 10.14800/rci.517.
11. Mehr-un-Nisa; Munawar A. Munawar; Yeon Sun Lee; David Rankin; Jawaria Munir; Josephine Lai; Misbahul A. Khan; Victor J. Hruby “Design, synthesis, and biological evaluation of a series of bifunctional ligands of Opioids/SSRIs” Bioorganic. Med. Chem. 2015, 23, 1251-1259.
12. Guillermo Martinez-Ariza; Jose Nunez-Rios; Yeon Sun Lee; Christopher Hulme “ Acetyl cyanide as a cyanide source in a tandem catalyst-free modified Groebke-Blackburn-Bienaym’s [4+1]-cycloaddition-Strecker cascade” Tetrahedron Lett., 2015, 56, 1038-1048.
13. Yeon Sun Lee; Sara M. Hall; Cyf Ramos-Colon; Michael Remesic; Lindsay LeBaron, Ann Nguyen; David Rankin, Frank Porreca; Josephine Lai; Victor J. Hruby “Modification of Amphipathic Non-opioid Dynorphin A Analogues for Rat Brain Bradykinin Receptors” Bioorg. Med. Chem. Lett., 2015, 25, 30-33.
14. Steve M. Fernandes; Yeon Sun Lee; Robert J. Gillies; Victor J. Hruby “Synthesis and evaluation of bivalent ligands for bidning to the human melanocortin-4 receptor” Bioorganic. Med. Chem., 2014, 22, 6360-6365.
15. Yeon Sun Lee; David Rankin; Sara M. Hall; Cyf Ramos-Colon; Jose J. Ortiz; Robert Kupp; Frank Porreca; Josephine Lai; Victor J. Hruby “Structure-activity relationships of non-opioid [des-Arg7]-dynorphin A analogues for bradykinin receptors” Bioorg. Med. Chem. Lett., 2014, 24, 4976-4979.
16. Kirsty Bannister; Yeon Sun Lee; Leonor Goncalves; Frank Porreca; Josephine Lai; Anthony H. Dickenson “Neuropathic plasticity in the opioid and non-opioid actions of dynorphin A fragments and their interactions with bradykinin B2 receptors on neuronal activity in the rat spinal cord” Neuropharmacology, 2014, 85, 375-383.
17. Yeon Sun Lee; Dhanasekaran Muthu; Sara M. Hal;, Cyf Ramos-Colon; David Rankin; Jackie Hu; Alexander J. Sandweiss; Milena De Felice; Jennifer Yanhua Xie,; Todd W. Vanderah; Frank Porreca; Josephine Lai; Victor J. Hruby “Discovery of Amphipathic Dynorphin A Analogues to Inhibit the Neuroexcitatory Effects of Dynorphin A through Bradykinin Receptors in the Spinal Cord” J. Am. Chem. Soc., 2014, 136, 6608-6616. (Selected as a Key Drug Discovery Article in Global Medical Discovery)
18. Alexander T. Podolsky; Alexander Sandweiss, Jackie Hu; Edward J. Bilsky; Jim P. Cain; Vlad K. Kumirov; Yeon Sun Lee; Victor J. Hruby; Ruben S. Vardanyan; Todd W. Vanderah “Novel fentanyl-based dual µ/δ–opioid agonists for the treatment of acute and chronic pain” Life Sci., 2013, 93, 1010-1016.
19. Yeon Sun Lee; Hongchang Qu; Peg Davis; Shou-wu Ma; Josephine Lai; Frank Porreca; Victor J. Hruby “Chiral effect of a phenylalanin in position 3 of the Dmt1-L(or D)-Tic2 pharmacophore on the opioid functional activities” ACS Med. Chem. Lett., 2013, 4, 656-659.
20. Ravil R. Petrov; Yeon Sun Lee; Ruben S. Vardanyan; Lu Liu; Shou-wu Ma; Peg Davis; Josephine Lai; Frank Porreca; Todd W. Vanderah; Victor J. Hruby “Effect of anchoring 4-anilidopiperidines to opioid peptides” Bioorg. Med. Chem. Lett., 2013, 23, 3434-3437.
21. Katherine E. Hanlon; Dave S. Herman; Richard S. Agnes; Tally M. Largent-Milnes; Isuru R. Kumarasinghe; Shou-wu Ma; Wenhong Guo; Yeon Sun Lee; Michael H. Ossipov; Victor J. Hruby; Josephine Lai; Frank Porreca; Todd W. Vanderah “Novel peptide ligands with dual acting pharmacophores designed for the pathophysiology of neuropathic pain’ Brain Res., 2011, 1395, 1-11.
22. Yeon Sun Lee; Vinod Kulkarani; Scott M. Cowell; Shou-wu Ma; Peg Davis; Katherine E. Hanlon; Todd W. Vanderah; Josephine Lai; Frank Porreca; Ruben Vardanyan; Victor J. Hruby “Development of poten µ and δ opioid agonists with high lipophilicity” J. Med. Chem., 2011, 54(1), 382-386. (Selected as “This week in therapeutics” of SciBX (Science-Business eXchange) by Nature publishing group.