Thursday, April 25, 2024
4/25/2024
The nicotinic acetylcholine receptor (nAChR) a7 subtype has numerous properties that distinguish it from other nAChRs, including activation by both the neurotransmitter ACh and the ubiquitous tissue factor choline, a feature that may be associated with its important functional expression in both neuronal and non-neuronal cells, including cells of the immune system. Expressed in such diverse tissues, a7 nAChR are also recognized as potentially important therapeutic targets for diverse indications including CNS disorders like Alzheimer's disease and schizophrenia, as well as peripheral disorders, especially inflammatory diseases and pain. Traditionally, study of a7 and other nAChRs has focused on ligands that activate or antagonize the receptor's ion channel; however, it has recently been shown that the best drugs for treating the peripheral disorders through the cholinergic anti-inflammatory pathway (CAP) may preferentially induce the alternative conformational states associated with ion channel desensitization. Consistent with the hypothesis that the selective targeting of a7 receptors for peripheral disorders requires qualitatively different drugs from those for CNS disorders, cells that mediate a7 control of inflammation do not have a7 receptors with activatible ion channels, possibly due to the co-expression of other gene products that limit ion channel function and confer distinct pharmacological profiles for a7 function in those cells. We have used electrophysiological, biochemical, and molecular biological approaches to determine how the multiple conformational states of a7 are selectively regulated by ligands, and we have used positive allosteric modulators (PAMs) to identify novel molecules that we characterized as silent agonists. These silent agonists are weak partial agonists in regards to channel activation but effective activators of CAP. Additionally, our studies of allosteric activators (ago- PAMs) and mutant receptors that cannot be activated by ACh or other orthosteric agonists has led to the identification of an allosteric agonist binding site and a new class of ligands that are PAM-dependent channel activators that also activate CAP. One aim will be to further characterize allosteric activators working with the structural scaffolds that we have identified, which include both potent small ligands and MrIC conotoxin. The conotoxin and mutants thereof will provide a template for the design of additional small ligands. We will also develop new ligands based on a novel sulfonium-based agonist that lacks a charged nitrogen and should have good brain penetration for indications of neuro-inflammatory pain and disease. We will test our new ligands and previously identified reference compounds in cell-based assays for the regulation of cytokine production and mediators of signal transduction that are relevant to inflammatory disease and pain. Data on the reference compounds will help define a target profile for new compounds. New compounds with desired cytokine profiles and good predicted pharmacokinetic properties will be moved forward into animal models of neuropathic and inflammatory pain. We will also test hypotheses related to accessory proteins that may differentially regulate a7 function in different cell types. We will then directly evaluate their efficacy in vivo for reducing pain from inflammation. These studies will allow us to test our core hypothesis that the therapeutic targeting of a7 for specific indications relies on identifying ligands that discriminate between channel-dependent and channel- independent signaling modes.
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