TY - JOUR T1 - Allosteric agonism of α7 nicotinic acetylcholine receptors JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.119.115758 SP - mol.119.115758 AU - Alican Gulsevin AU - Roger L Papke AU - Clare Stokes AU - Sumanta Garai AU - Ganesh A Thakur AU - Marta Quadri AU - Nicole Horenstein Y1 - 2019/01/01 UR - http://molpharm.aspetjournals.org/content/early/2019/04/04/mol.119.115758.abstract N2 - Nicotinic acetylcholine receptors (nAChR) are members of the Cys-loop superfamily of ligand-gated ion channels. Typically, channel activation follows the binding of agonists to the orthosteric binding sites of the receptor. α7 nAChR have a very low probability of channel activation, which can be reversed by the binding of α7-selective positive allosteric modulators (PAMs) to putative sites within the transmembrane domains. While typical PAMs, like PNU-120596 require co-application of an orthosteric agonist to produce large channel activations, some, like GAT107 and B-973B, are characterized as ago-PAMs, which also bind to an allosteric activation (AA) site in the extracellular domain and activate the α7 ion channel by themselves. We had previously characterized N,N-diethyl-N'-phenylpiperazine (diEPP) analogs with various functions. In this work, we docked members of this family to a homology model of the α7 receptor extracellular domain. The compound 1,1-diethyl-4(naphthalene-2-yl)piperazin-1-ium (2NDEP) a weak partial agonist, showed particularly favorable docking and binding energies at the putative AA site of the receptor. We hypothesized that 2NDEP could couple with PAMs through the AA site. This hypothesis was tested with the α7 mutant C190A, which is not activated by orthosteric agonists but is effectively activated by GAT107. The results showed that 2NDEP acts as an allosteric agonist of α7C190A when co-applied with the PAM PNU-120596. Also, the allosteric activity was nearly abolished upon co-application with the AA site-selective antagonist 2,3,5,6MP-TQS, consistent with AA site involvement. Overall, our findings show a novel mode of agonism through an allosteric site in the extracellular domain of α7 nAChR. ER -