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)
Research Project (R01)
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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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Bagdas, Deniz; Wilkerson, Jenny L; Kulkarni, Abhijit et al. (2016) The α7 nicotinic receptor dual allosteric agonist and positive allosteric modulator GAT107 reverses nociception in mouse models of inflammatory and neuropathic pain. Br J Pharmacol 173:2506-20
Quadri, Marta; Papke, Roger L; Horenstein, Nicole A (2016) Dissection of N,N-diethyl-N'-phenylpiperazines as α7 nicotinic receptor silent agonists. Bioorg Med Chem 24:286-93
Horenstein, Nicole A; Papke, Roger L; Kulkarni, Abhijit R et al. (2016) Critical Molecular Determinants of α7 Nicotinic Acetylcholine Receptor Allosteric Activation: SEPARATION OF DIRECT ALLOSTERIC ACTIVATION AND POSITIVE ALLOSTERIC MODULATION. J Biol Chem 291:5049-67
Hillmer, A T; Esterlis, I; Gallezot, J D et al. (2016) Imaging of cerebral α4β2* nicotinic acetylcholine receptors with (-)-[(18)F]Flubatine PET: Implementation of bolus plus constant infusion and sensitivity to acetylcholine in human brain. Neuroimage 141:71-80
van Maanen, Marjolein A; Papke, Roger L; Koopman, Frieda A et al. (2015) Two novel α7 nicotinic acetylcholine receptor ligands: in vitro properties and their efficacy in collagen-induced arthritis in mice. PLoS One 10:e0116227
Papke, Roger L; Bagdas, Deniz; Kulkarni, Abhijit R et al. (2015) The analgesic-like properties of the alpha7 nAChR silent agonist NS6740 is associated with non-conducting conformations of the receptor. Neuropharmacology 91:34-42
Stokes, Clare; Treinin, Millet; Papke, Roger L (2015) Looking below the surface of nicotinic acetylcholine receptors. Trends Pharmacol Sci 36:514-23
Papke, Roger L; Horenstein, Nicole A; Stokes, Clare (2015) Nicotinic Activity of Arecoline, the Psychoactive Element of ""Betel Nuts"", Suggests a Basis for Habitual Use and Anti-Inflammatory Activity. PLoS One 10:e0140907
Bordia, Tanuja; McGregor, Matthew; Papke, Roger L et al. (2015) The α7 nicotinic receptor agonist ABT-107 protects against nigrostriatal damage in rats with unilateral 6-hydroxydopamine lesions. Exp Neurol 263:277-84
Papke, Roger L; Chojnacka, Kinga; Horenstein, Nicole A (2014) The minimal pharmacophore for silent agonism of the α7 nicotinic acetylcholine receptor. J Pharmacol Exp Ther 350:665-80

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