Neonicotinic analogues: Selective antagonists for α4β2 nicotinic acetylcholine receptors

Manuel Faundez-Parraguez, Nicolas Farias-Rabelo, Juan Pablo Gonzalez-Gutierrez, Alvaro Etcheverry-Berrios, Jans Alzate-Morales, Francisco Adasme-Carreño, Rodrigo Varas, Isabel Bermudez, Patricio Iturriaga-Vasquez*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Nicotine is an agonist of nicotinic acetylcholine receptors (nAChRs) that has been extensively used as a template for the synthesis of α4β2-preferring nAChRs. Here, we used the N-methyl-pyrrolidine moiety of nicotine to design and synthesise novel α4β2-preferring neonicotinic ligands. We increased the distance between the basic nitrogen and aromatic group of nicotine by introducing an ester functionality that also mimics acetylcholine (Fig. 2). Additionally, we introduced a benzyloxy group linked to the benzoyl moiety. Although the neonicotinic compounds fully inhibited binding of both [α-125I]bungarotoxin to human α7 nAChRs and [3H]cytisine to human α4β2 nAChRs, they were markedly more potent at displacing radioligand binding to human α4β2 nAChRs than to α7 nAChRs. Functional assays showed that the neonicotinic compounds behave as antagonists at α4β2 and α4β2α5 nAChRs. Substitutions on the aromatic ring of the compounds produced compounds that displayed marked selectivity for α4β2 or α4β2α5 nAChRs. Docking of the compounds on homology models of the agonist binding site at the α4/β2 subunit interfaces of α4β2 nAChRs suggested the compounds inhibit function of this nAChR type by binding the agonist binding site.

Original languageEnglish
Pages (from-to)2687-2694
Number of pages8
JournalBioorganic and Medicinal Chemistry
Issue number10
Publication statusPublished - 15 May 2013

Keywords / Materials (for Non-textual outputs)

  • Antagonism
  • Functional and affinities
  • Nicotinic acetylcholine receptors
  • Structure-activity relationships


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