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TrpB is one of five residues that form the aromatic box of the agonist binding site, and for the prototype agonists ACh and nicotine, only TrpB makes a functional cation-\u03c0 interaction. We report that, in addition to TrpB, a significant cation-\u03c0 interaction is made to a second aromatic, TyrC2, by the agonists metanicotine, TC299423, varenicline, and nornicotine. A common structural feature of these agonists, and a distinction from ACh and nicotine, is a protonated secondary amine that provides the cation for the cation-\u03c0 interaction. These results indicate a distinction in binding modes between agonists with subtly different structures that may provide guidance for the development of subtype-selective agonists of nAChRs.<\/jats:p>","DOI":"10.1523\/eneuro.0032-17.2017","type":"journal-article","created":{"date-parts":[[2017,3,18]],"date-time":"2017-03-18T03:05:07Z","timestamp":1489806307000},"page":"ENEURO.0032-17.2017","source":"Crossref","is-referenced-by-count":13,"title":["Secondary Ammonium Agonists Make Dual Cation-\u03c0 Interactions in \u03b14\u03b22 Nicotinic Receptors"],"prefix":"10.1523","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3214-7619","authenticated-orcid":false,"given":"Michael R.","family":"Post","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabrielle 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