The a7 nicotinic acetylcholine receptor is being energetically pursued as a drug target for diverse disorders, from Alzheimer's disease to septic shock. We have demonstrated that there are at least three distinct structural motifs which can be used to modify a core agonist structure, such as anabaseine or quinuclidine, to achieve a7 selectivity. For example, selectivity can be achieved through modification of the core agonist with the addition of a large hydrophobic side group such as a benzene ring. The precise chemical structure of the hydrophobic side group determines efficacy and potency, as well as another key feature, the ability to produce stable ion channel desensitization following a transient phase of ion channel activation. The desensitization is due to prolonged binding to the receptor, and the desensitizing properties of specific agents are likely to impact their therapeutic utility for specific indications. We show that drugs which desensitize and do not activate the receptor ion channel can still be effective at treating inflammatory diseases. We will use mammalian cells transfected with a7 alone, or in combination with pro-inflammatory cytokine receptors to test the hypothesis that drugs which induce stable desensitization of the a7 ion channel may still be effective at mediating ion channel independent signal transduction through the intracellular JAK/STAT pathway. We will also test the hypothesis that ion channel activation, in contrast, is essential for the enhancement of LTP, a memory-related process in the hippocampus. We have generated models for how the various a7-agonists dock in the ligand- binding domain of the a7 receptor and have identified amino acids which we hypothesize will have point-to- point interactions with substituents on the hydrophobic side groups of the a7-selective agonists. We will investigate the potential importance of hydrogen bonding and hydrophobic interactions on the binding, gating, and desensitizing properties of the specific receptor/ligand combinations. We will test our hypotheses with site-directed mutations, as well as with novel a7-selective ligands that will be restricted in their ability to form specific point-to-point interactions, for example, agents which are only able to be H-bond donors or acceptors. Wild-type and mutant receptors will be expressed in either Xenopus oocytes or transfected mammalian cells, and we will study ion channel properties by measuring both whole-cell and single-channel currents. We will use the Type 2 positive allosteric modulator PNU-120596 to measure the desensitizing properties of specific ligands and to overcome the intrinsically limited open probability of a7 receptors, making their single-channel currents more amenable to study. We will use tkP3BzPB, a novel highly selective a7 noncompetitive antagonist, to separate ion channel activation dependent and independent forms of signal transduction, and to further manipulate ion channel open probability. Together these studies will provide important advancements leading to the design of a7 agonists with optimized profiles of pharmacological properties for specific indications.

Public Health Relevance

There are many types of nicotine receptors in the brain, and only some of them are related to why people become addicted to nicotine. One type of nicotine receptor that is not the cause of addiction is the alpha7-type receptor, and stimulation of this receptor combats conditions like schizophrenia, Alzheimer's disease, septic shock and other inflammatory diseases. We have identified drugs that will selectively stimulate alpha7 receptors in one of two different ways. One form of stimulation may help alleviate brain diseases;the other may help alleviate diseases like arthritis. We will use our new discoveries about how these drugs work to help make alpha7-stimulating drugs optimally designed to treat specific diseases.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
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Dunsmore, Sarah
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University of Florida
Schools of Medicine
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Papke, Roger L; Chojnacka, Kinga; Horenstein, Nicole A (2014) The minimal pharmacophore for silent agonism of the ?7 nicotinic acetylcholine receptor. J Pharmacol Exp Ther 350:665-80
Papke, Roger L; Horenstein, Nicole A; Kulkarni, Abhijit R et al. (2014) The activity of GAT107, an allosteric activator and positive modulator of *7 nicotinic acetylcholine receptors (nAChR), is regulated by aromatic amino acids that span the subunit interface. J Biol Chem 289:4515-31
Brunzell, Darlene H; McIntosh, J Michael; Papke, Roger L (2014) Diverse strategies targeting ?7 homomeric and ?6?2* heteromeric nicotinic acetylcholine receptors for smoking cessation. Ann N Y Acad Sci 1327:27-45
Papke, Roger L (2014) Merging old and new perspectives on nicotinic acetylcholine receptors. Biochem Pharmacol 89:1-11
Thakur, Ganesh A; Kulkarni, Abhijit R; Deschamps, Jeffrey R et al. (2013) Expeditious synthesis, enantiomeric resolution, and enantiomer functional characterization of (4-(4-bromophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide (4BP-TQS): an allosteric agonist-positive allosteric modulator of *7 nicotinic ac J Med Chem 56:8943-7
Peng, Can; Kimbrell, Matthew R; Tian, Chengju et al. (2013) Multiple modes of *7 nAChR noncompetitive antagonism of control agonist-evoked and allosterically enhanced currents. Mol Pharmacol 84:459-75
Papke, Roger L; Stokes, Clare; Muldoon, Pretal et al. (2013) Similar activity of mecamylamine stereoisomers in vitro and in vivo. Eur J Pharmacol 720:264-75
Chojnacka, Kinga; Papke, Roger L; Horenstein, Nicole A (2013) Synthesis and evaluation of a conditionally-silent agonist for the *7 nicotinic acetylcholine receptor. Bioorg Med Chem Lett 23:4145-9
Isaacson, Matthew D; Horenstein, Nicole A; Stokes, Clare et al. (2013) Point-to-point ligand-receptor interactions across the subunit interface modulate the induction and stabilization of conformational states of alpha7 nAChR by benzylidene anabaseines. Biochem Pharmacol 85:817-28
Peng, Can; Stokes, Clare; Mineur, Yann S et al. (2013) Differential modulation of brain nicotinic acetylcholine receptor function by cytisine, varenicline, and two novel bispidine compounds: emergent properties of a hybrid molecule. J Pharmacol Exp Ther 347:424-37

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