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Structure‐Guided Design for Agonist Selectivity with α7‐nAChRs
Author(s) -
CamachoHernandez Gisela Andrea,
Kaczanowska Katarzyna,
Harel Michal,
Beck Christina,
Doan Lisa,
Binding Hanna,
Taylor Palmer
Publication year - 2017
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.31.1_supplement.663.3
Subject(s) - chemistry , nicotinic agonist , acetylcholine receptor , nicotinic acetylcholine receptor , agonist , ligand (biochemistry) , protein subunit , epibatidine , binding site , acetylcholine , stereochemistry , biophysics , receptor , biochemistry , pharmacology , biology , gene
Nicotinic acetylcholine receptors (nAChRs) are ligand‐gated ion channels present in the peripheral and central nervous systems. Pre‐ and post‐synaptic nAChRs modulate CNS functions, and ligands selective for nAChR subtype may form useful therapies for disorders associated with development and aging of the nervous system. We have developed a small sub‐group of 4,6 di‐substituted 2‐aminopyrimidines that interact with the acetylcholine binding protein (AChBP) and activate α7‐nAChRs. These agents show Kd and Ka values for both AChBP binding and α7‐nAChR activation between 10 and 70nM. To examine the structural basis of agonist selectivity, we employ measurements of ligand binding to AChBP, and analysis of ligand binding poses from X‐ray crystal structures, along with α7‐nAChR activation on intact cells in culture. Crystal structures suggest a distinct binding pose is required for α7‐nAChR activation enabling us to define the molecular determinants giving rise to activation and selectivity for the α7 subtype. By combining the picolyl substitution at the 4‐position of the pyrimidine and departing from the symmetry of the molecule, we are able to discriminate between α7 activation and generalized binding at the subunit interface. The 4,6‐disubstituted 2‐aminopyrimidines have high selectivity for α7‐nAChR. Crystallography studies using the soluble acetylcholine binding protein (AChBP), a surrogate protein of the extracellular domain of α7‐nAChR, reveal three distinctive binding interactions and poses of nicotinic agonists: 1) cation‐π interactions for quaternary amines and an aromatic nest of side chains at the subunit interface, 2) stabilization of secondary amines and imines by a hydrogen bond from its protonated basic nitrogen to the backbone carbonyl of a conserved tryptophan on the principal subunit face, 3) interaction of less basic multi‐ring pyrimidine‐pyridine heterocycles at the binding interface. This new family of 2‐aminopyrimidines enables us to define receptor subtype selectivity and achieve a structural landscape for α7 selective activation amongst a plethora of CNS nAChR subtypes. Support or Funding Information NIH Grant GM 18360‐44