The minimum pharmacophore for activation of the human alpha 7 nicotinic acetylcholine receptor (nAChR) is the tetramethylammonium cation.  Previous work demonstrated that larger quaternary ammonium compounds such as diethyl dimethylammonium cation or N-methyl quinuclidine were alpha7-selective partial agonists, but additional increase in the size of the N-alkyl group by a single carbon to an N-ethyl group led to a loss of this activity.  We report that, while such compounds are ineffective at inducing the normal channel open state, they nonetheless regulate the induction of specific conformational states. 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 the receptor's preferred distribution amongst conformational states including partial agonism, competitive antagonism, a non-conducting state that could be converted to an activated state by a positive allosteric modulator (PAM), or a PAM-insensitive non-conducting state.  We hypothesize that the changes of molecular volume subtly impact interactions at the subunit interface constituting the orthosteric binding site in such a way as to determine state distribution. We define a new minimal pharmacophore for the class of compounds we have termed as �silent agonists�, which are able to induce allosteric modulator-dependant activation but not the normal activated state.

a7 nAChr state distribution controlled by quaternary ammonium ligands

248th National Meeting (2014)

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