Synthesis of selective agonists for the α7 nicotinic acetylcholine receptor with in situ click-chemistry on acetylcholine-binding protein templates

John G. Yamauchi, Kimberly Gomez, Neil Grimster, Mikael Dufouil, Ákos Nemecz, Joseph R. Fotsing, Kwok Yiu Ho, Todd T. Talley, K. Barry Sharpless, Valery V. Fokin, Palmer Taylor

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Abstract

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 catalysis of in situ azide-alkyne cycloaddition reactions at a dynamic subunit interface facilitated the synthesis of potentially selective compounds for nAChRs. We investigated compound sets generated in situ with soluble AChBP templates through pharmacological characterization with α7 and α4β2 nAChRs and 5-hydroxytryptamine type 3A receptors. Analysis of activity differences between the triazole 1,5-synand 1,4-anti-isomers showed a preference for the 1,4-antitriazole regioisomers among nAChRs. To improve nAChR subtype selectivity, the highest-potency building block for α7 nAChRs, i.e., 3α-azido-N-methylammonium tropane, was used for additional in situ reactions with a mutated Aplysia californica AChBP that was made to resemble the ligand-binding domain of the α7 nAChR. Fourteen of 50 possible triazole products were identified, and their corresponding tertiary analogs were synthesized. Pharmacological assays revealed that the mutated binding protein template provided enhanced selectivity of ligands through in situ reactions. Discrete trends in pharmacological profiles were evident, with most compounds emerging as α7 nAChR agonists and α4β2 nAChR antagonists. Triazoles bearing quaternary tropanes and aromatic groups were most potent for α7 nAChRs. Pharmacological characterization of the in situ reaction products established that click-chemistry synthesis with surrogate receptor templates offered novel extensions of fragment-based drug design that were applicable to multisubunit ion channels.

Original languageEnglish
Pages (from-to)687-699
Number of pages13
JournalMolecular Pharmacology
Volume82
Issue number4
DOIs
Publication statusPublished - Oct 2012
Externally publishedYes

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ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine

Cite this

Yamauchi, J. G., Gomez, K., Grimster, N., Dufouil, M., Nemecz, Á., Fotsing, J. R., Ho, K. Y., Talley, T. T., Sharpless, K. B., Fokin, V. V., & Taylor, P. (2012). Synthesis of selective agonists for the α7 nicotinic acetylcholine receptor with in situ click-chemistry on acetylcholine-binding protein templates. Molecular Pharmacology, 82(4), 687-699. https://doi.org/10.1124/mol.112.080291