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Ligand design for human nicotinic acetylcholine receptors using in situ freeze‐frame click chemistry
Author(s) -
Yamauchi John,
Nemecz Akos,
Ho KwokYiu,
Fotsing Joseph R.,
Weide Timo,
Grimster Neil,
Stump Bernhard,
Talley Todd T.,
Fokin Valery V.,
Sharpless K. Barry,
Taylor Palmer
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.579.2
Subject(s) - nicotinic agonist , acetylcholine receptor , ionotropic effect , chemistry , methyllycaconitine , receptor , acetylcholine , ion channel , muscarinic acetylcholine receptor , ligand gated ion channel , epibatidine , ganglion type nicotinic receptor , biophysics , nicotinic acetylcholine receptor , pharmacology , neuroscience , biochemistry , biology , nmda receptor
Nicotinic acetylcholine receptors (nAChRs) are ionotropic receptors activated by acetylcholine in synapses of the CNS, neuromuscular junctions, and autonomic ganglia. The α4β2 and α7 nAChR subtypes are therapeutic targets for smoking cessation and treatment of schizophrenia. We developed a structure‐guided design strategy utilizing the Aplysia californica and Lymnaea stagnalis acetylcholine binding proteins (AChBPs) as homologous structural surrogates for the nicotinic receptor extracellular domain. We show that in situ click chemistry can be performed at subunit interfaces to generate selective nAChR agonists and antagonists. Lead compounds can then be refined through catalytic synthesis of close triazole congeners on a submilligram scale to assay AChBP template affinity and pharmacological activity on α4β2 and α7 nAChRs. Responses to other receptors that are potential complementary or “off targets” for the compounds were measured including α1 nAChR, 5‐HT 3A and M1 muscarinic receptors. Crystallography of AChBP with the compounds was implemented to identify determinants involved in agonist or antagonist responses. The results of the functional and binding responses suggest that in situ freeze‐frame click chemistry can be a powerful tool in the future for developing specific ligands of various receptors. (Support from R37‐GM18360, UO1‐DA019372, NSF GK12 0742551)