Opioid analgesics, such as morphine, hydromorphone and fentanyl, are broadly prescribed for the management of acute, post-operative and chronic pain. Despite this widespread clinical use, a number of side effects persist including drowsiness, confusion, nausea, hyperalgesia and respiratory depression. Opioids are also highly addictive, and considered drugs of abuse by the NIDA. We wish to develop new pharmacological tools for interrogating specific biochemical mechanisms that underlie pain sensation with the longer-term goal of revealing next-generation therapeutics for pain treatment. Voltage-gated Na+ ion channels are integral membrane proteins responsible for electrical communication between cells. Ten mammalian genes have been sequenced that encode for ten different channel isoforms (NaV1.1- 1.9 and NaX), each having unique biophysical characteristics, and cellular and tissue distribution patterns. Drugs that inhibit NaVs non-specifically (e.g., lidocaine) find application as short-lasting, local anesthetics, but are less than desirable for any type of systemic or chronic use. A compelling body of evidence, however, suggests that specific inhibition of a single NaV isoform could reduce pain sensitivity without the accompanying side effects (numbness, ataxia) associated with local anesthetic treatments (and without chance of addiction, as noted with opioids). Similarities in the macromolecular structures of the nine NaV isoforms have thwarted most efforts to develop drugs that function as antagonist against only a single channel subtype. Our approach will capitalize on the highly specific binding of a monoclonal antibody engineered to target a single NaV isoform. We envision utilizing antibodies raised against NaV1.7, a channel isoform of particular interest as a target for pain treatment. Ion conduction will be inhibited by covalently linking to this antibody a potent, small molecule channel antagonist. Saxitoxin is a low molecular weight, naturally occurring product that acts with nanomolar potency on NaV1.1-1.4, 1.6, and 1.7 by lodging in the outer mouth of the channel pore. Strategies will be developed for conjugating modified forms of (+)-saxitoxin to the antibody and for testing the efficacy of these agents as isoform-specific blockers of NaV function. The success of this program will provide: 1) a tool that can be used to validate NaV1.7 as a target for pain treatment;2) a novel therapeutic lead in the form of an antibody-small molecule conjugate;and 3) a blueprint for preparing specific inhibitors of other NaV isoforms.
Opioid analgesics, such as morphine, cause a range of side effects and are subject to abuse, yet remain the most frequently prescribed drugs for the treatment of pain. We wish to develop new pharmacological tools that act by intervening with specific pain-producing signals in order to gain a deeper understanding of the etiology of pain. Results from these studies could help guide the development of next-generation therapies for pain management.
| Thottumkara, Arun P; Parsons, William H; Du Bois, J (2014) Saxitoxin. Angew Chem Int Ed Engl 53:5760-84 |
| Parsons, William H; Du Bois, J (2013) Maleimide conjugates of saxitoxin as covalent inhibitors of voltage-gated sodium channels. J Am Chem Soc 135:10582-5 |
| Walker, James R; Novick, Paul A; Parsons, William H et al. (2012) Marked difference in saxitoxin and tetrodotoxin affinity for the human nociceptive voltage-gated sodium channel (Nav1.7) [corrected]. Proc Natl Acad Sci U S A 109:18102-7 |
