RT Journal Article SR Electronic T1 Synthesizing Selective Agonists for the α7 Nicotinic Receptor with in situ Click-Chemistry on Acetylcholine Binding Protein Templates JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP mol.112.080291 DO 10.1124/mol.112.080291 A1 John G. Yamauchi A1 Kimberly Gomez A1 Neil Grimster A1 Mikael Dufouil A1 Akos Nemecz A1 Joseph R Fotsing A1 Kwok-Yiu Ho A1 Todd T Talley A1 K. Barry Sharpless A1 Valery V Fokin A1 Palmer Taylor YR 2012 UL http://molpharm.aspetjournals.org/content/early/2012/07/11/mol.112.080291.abstract AB The acetylcholine binding proteins (AChBPs), which serve as structural surrogates for the extracellular domain of nicotinic acetylcholine receptors (nAChRs), were used as reaction templates for in situ click-chemistry reactions to generate a congeneric series of triazoles from azide and alkyne building blocks. The recent achievement of catalyzing in situ azide-alkyne cycloaddition reactions at a dynamic subunit interface facilitates synthesis of potentially selective compounds for nAChRs. We investigate compound sets generated in situ at soluble AChBP templates with receptor targets through their pharmacological characterization at α7 and α4β2-nAChRs as well as 5-HT3A receptors. Analysis of activity differences between (1,5)-syn and (1,4)-anti triazole isomers showed a preference towards the (1,4)-anti triazole regioisomer among nAChRs. To improve nAChR subtype selectivity, the highest potency building block for α7-nAChRs, 3α-azido N-methylammonium tropane, was utilized for additional in situ reactions using a mutated Aplysia californica AChBP, made to resemble the ligand binding domain of the α7-nAChR. Fourteen of fifty possible triazole products were identified and their corresponding tertiary analogues synthesized. Pharmacological assays revealed that the mutated binding protein template provided enhanced selectivity of ligands through in situ reactions. Discrete trends in pharmacological profiles are evident with most compounds emerging as α7-nAChR agonists and α4β2-nAChR antagonists. Triazoles bearing quaternary tropanes and aromatic groups were most potent for the α7-nAChR. Pharmacological characterization of the in situ reaction products establish that click-chemistry synthesis, guided with surrogate receptor templates offers novel extensions of fragment-based drug design applicable to multi-subunit ion channels.