PT - JOURNAL ARTICLE AU - Roger L. Papke AU - Kinga Chojnacka AU - Nicole A. Horenstein TI - The Minimal Pharmacophore for Silent Agonism of the <em>α</em><sub>7</sub> Nicotinic Acetylcholine Receptor AID - 10.1124/jpet.114.215236 DP - 2014 Sep 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 665--680 VI - 350 IP - 3 4099 - http://jpet.aspetjournals.org/content/350/3/665.short 4100 - http://jpet.aspetjournals.org/content/350/3/665.full SO - J Pharmacol Exp Ther2014 Sep 01; 350 AB - The minimum pharmacophore for activation of the human α7 nicotinic acetylcholine receptor (nAChR) is the tetramethylammonium cation. Previous work demonstrated that larger quaternary ammonium compounds, such as diethyldimethylammonium or 1-methyl quinuclidine, were α7-selective partial agonists, but additional increase in the size of the ammonium cation or the quinuclidine N-alkyl group by a single carbon to an N-ethyl group led to a loss of efficacy for ion channel activation. We report that although such compounds are ineffective at inducing the normal channel open state, they nonetheless regulate the induction of specific conformational states normally considered downstream of channel activation. We synthesized several panels of quaternary ammonium nAChR ligands that systematically varied the size of the substituents bonded to the central positively charged nitrogen atom. In these molecular series, we found a correlation between the molecular volume of the ligand and/or charge density, and the receptor’s preferred distribution among conformational states including the closed state, the active state, a nonconducting state that could be converted to an activated state by a positive allosteric modulator (PAM), and a PAM-insensitive nonconducting state. We hypothesize that the changes of molecular volume of an agonist’s cationic core subtly impact interactions at the subunit interface constituting the orthosteric binding site in such a way as to regulate the probability of conversions among the conformational states. We define a new minimal pharmacophore for the class of compounds we have termed “silent agonists,” which are able to induce allosteric modulator-dependent activation but not the normal activated state.