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.
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.
|Papke, Roger L; Peng, Can; Kumar, Ashok et al. (2018) NS6740, an ?7 nicotinic acetylcholine receptor silent agonist, disrupts hippocampal synaptic plasticity. Neurosci Lett 677:6-13|
|Quadri, Marta; Bagdas, Deniz; Toma, Wisam et al. (2018) The Antinociceptive and Anti-Inflammatory Properties of the ?7 nAChR Weak Partial Agonist p-CF3N,N-diethyl-N'-phenylpiperazine. J Pharmacol Exp Ther 367:203-214|
|Papke, Roger L; Stokes, Clare; Damaj, M Imad et al. (2018) Persistent activation of ?7 nicotinic ACh receptors associated with stable induction of different desensitized states. Br J Pharmacol 175:1838-1854|
|Bagdas, Deniz; Gurun, Mine S; Flood, Pamela et al. (2018) New Insights on Neuronal Nicotinic Acetylcholine Receptors as Targets for Pain and Inflammation: A Focus on ?7 nAChRs. Curr Neuropharmacol 16:415-425|
|Jackson, Asti; Papke, Roger L; Damaj, M Imad (2018) Pharmacological modulation of the ?7 nicotinic acetylcholine receptor in a mouse model of mecamylamine-precipitated nicotine withdrawal. Psychopharmacology (Berl) 235:1897-1905|
|Abbas, Muzaffar; Alzarea, Sami; Papke, Roger L et al. (2017) The ?7 nicotinic acetylcholine receptor positive allosteric modulator attenuates lipopolysaccharide-induced activation of hippocampal I?B and CD11b gene expression in mice. Drug Discov Ther 11:206-211|
|Treinin, Millet; Papke, Roger L; Nizri, Eran et al. (2017) Role of the ?7 Nicotinic Acetylcholine Receptor and RIC-3 in the Cholinergic Anti-inflammatory Pathway. Cent Nerv Syst Agents Med Chem 17:90-99|
|Quadri, Marta; Stokes, Clare; Gulsevin, Alican et al. (2017) Sulfonium as a Surrogate for Ammonium: A New ?7 Nicotinic Acetylcholine Receptor Partial Agonist with Desensitizing Activity. J Med Chem 60:7928-7934|
|Horenstein, Nicole A; Quadri, Marta; Stokes, Clare et al. (2017) Cracking the Betel Nut: Cholinergic Activity of Areca Alkaloids and Related Compounds. Nicotine Tob Res :|
|Donvito, Giulia; Bagdas, Deniz; Toma, Wisam et al. (2017) The interaction between alpha 7 nicotinic acetylcholine receptor and nuclear peroxisome proliferator-activated receptor-? represents a new antinociceptive signaling pathway in mice. Exp Neurol 295:194-201|
Showing the most recent 10 out of 81 publications