title: The analgesic-like properties of the alpha7 nAChR silent agonist NS6740 is associated with non-conducting conformations of the receptor.
abstract: The α7 nicotinic acetylcholine receptor (nAChR) is a promising drug target for a number of neurological disorders including chronic pain and inflammatory diseases. Since α7 can function as a ligand-gated ion channel, drug development initially focused on ligands that were selective activators of the α7 ion channel. However, the best α7 drugs for chronic pain and inflammation indications may not be ion channel activators but rather "silent agonists", which bind to the receptor but preferentially induce non-conducting states that modulate signal transduction in non-neuronal cells. One such compound is NS6740. We show that NS6740 selectively induces prolonged desensitization of α7 nAChRs. There are two forms of α7 desensitization that can be distinguished by their sensitivity to the positive allosteric modulators (PAMs). At high concentrations, NS6740 preferentially induces PAM-insensitive desensitization, which over the course of several minutes reverts to the sensitive form. NS6740 was tested in several pain models after in vivo administration in the mouse. Although it had no effects in acute thermal pain, NS6740 induced significant dose- and time-dependent antinociceptive activity in formalin- and acetic acid-induced nociceptive behaviors as well as in the chronic constrictive nerve injury (CCI) model for neuropathic pain. The antinociceptive activity of NS6740 in these models was α7-dependent. In addition, NS6740 administration reversed pain-induced aversion, an important affective component of pain. The time and concentration dependence of the effects were consistent with NS6740 induction of PAM-insensitive non-conducting states, suggesting that signal transduction required for analgesia is accomplished by α7 receptors in that conformation.
authors.affiliation: Department of Pharmacology and Therapeutics, University of Florida, PO Box 100267, Gainesville, FL 32610-0267, USA.
authors.forename: Roger L
authors.initials: RL
authors.lastname: Papke
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA 23298-0613, USA; Experimental Animals Breeding and Research Center, Faculty of Medicine, Uludag University, Bursa, 16059, Turkey. Electronic address: dbagdas@vcu.edu.
authors.forename: Deniz
authors.initials: D
authors.lastname: Bagdas
authors.affiliation: Department of Pharmaceutical Sciences & Center for Drug Discovery, Northeastern University, Boston, MA 02115, USA.
authors.forename: Abhijit R
authors.initials: AR
authors.lastname: Kulkarni
authors.affiliation: Department of Chemistry, University of Florida, PO Box 117200, Gainesville, FL 32611-7200, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Gould
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Kingdom of Saudi Arabia.
authors.forename: Shakir D
authors.initials: SD
authors.lastname: AlSharari
authors.affiliation: Department of Pharmaceutical Sciences & Center for Drug Discovery, Northeastern University, Boston, MA 02115, USA.
authors.forename: Ganesh A
authors.initials: GA
authors.lastname: Thakur
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA 23298-0613, USA.
authors.forename: M Imad
authors.initials: MI
authors.lastname: Damaj
mesh_terms: D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage*; D000818:Animals; D053961:Azabicyclo Compounds / Q000008:administration & dosage*; D005663:Furans / Q000008:administration & dosage*; D006801:Humans; D008297:Male; D008813:Mice, Inbred ICR; D009437:Neuralgia / Q000188:drug therapy*; D017288:Pain Threshold / Q000187:drug effects; D011487:Protein Conformation / Q000187:drug effects*; D021122:Protein Subunits; D014981:Xenopus; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000819:agonists* / Q000235:genetics / Q000502:physiology*
chemical_list: C547286:1,4-diazabicyclo(3.2.2)nonan-4-yl(5-(3-(trifluoromethyl)phenyl)furan-2-yl)methanone; D018712:Analgesics, Non-Narcotic; D053961:Azabicyclo Compounds; D005663:Furans; D021122:Protein Subunits; D064569:alpha7 Nicotinic Acetylcholine Receptor
keywords: Inflammatory pain; Neuropathic pain; Nicotinic acetylcholine receptors; Silent agonist; alpha7