The minimal pharmacophore for silent agonism of alpha7 nAChR.

The Journal of pharmacology and experimental therapeutics

PubMedID: 24990939

Papke RL, Chojnacka K, Horenstein NA. The minimal pharmacophore for silent agonism of alpha7 nAChR. J Pharmacol Exp Ther. 2014;.
The minimum pharmacophore for activation of the human a7 nicotinic acetylcholine receptor (nAChR) is the tetramethylammonium cation. Previous work demonstrated that larger quaternary ammonium compounds such as diethyl-dimethylammonium or N-methyl quinuclidine were a7-selective partial agonists, but additional increase in the size of the simple 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, while 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 amongst conformational states including the closed state, the active state, a non-conducting state that could be converted to an activated state by a positive allosteric modulator (PAM), and a PAM-insensitive non-conducting 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 as "silent agonists", which are able to induce allosteric modulator-dependent activation but not the normal activated state.