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Structure‐Activity Relationships of Selective Pyrimidine Agonists on α7‐nAChRs
Author(s) -
Hernandez Gisela Andrea Camacho,
Kaczanowska Katarzyna,
Brandao Stefania,
Stokes Clare,
Papke Roger Lee,
Taylor Palmer
Publication year - 2019
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.2019.33.1_supplement.667.9
Subject(s) - nicotinic agonist , acetylcholine receptor , chemistry , agonist , xenopus , acetylcholine , ligand gated ion channel , biophysics , receptor , nicotinic acetylcholine receptor , protein subunit , methyllycaconitine , alpha 4 beta 2 nicotinic receptor , pharmacology , neuroscience , ion channel , biochemistry , biology , gene
Nicotinic acetylcholine receptors (nAChRs) are prototypic pentameric ligand‐gated ion channels (pLGIC), activated by the endogenous neurotransmitter acetylcholine. nAChRs are present in the peripheral and central nervous systems, where they modulate central, peripheral autonomic and neuromuscular functions. One of the most abundant neuronal nAChRs is the homopentameric α7. This subtype comprises of five identical α7 subunits with five binding sites, located between the subunit interfaces. The α7‐nAChR has a relatively low affinity for nicotine and acetylcholine, and a high permeability for Ca +2 . Activation occurs on sub‐millisecond time scale; desensitization occurs upon prolonged application of agonist. nAChRs are found on presynaptic terminals in brain mediating the release of other neurotransmitters. We previously synthesized a family of 4,6 substituted 2‐aminopyrimidines; our lead candidate, AC‐171A2, activates selectively the α7‐nAChRswith an EC 50 of 70nM in the presence of PNU‐120596, diverging from classical agonist on binding interaction as well as chemical components. This compound has an EC 50 of 360nM when fast activation was evaluated in a Xenopus oocyte system without PNU‐120596. When recovery of the receptor was assessed, AC‐171A2 allowed full recovery at 3mM concentration after 12 min. One of the goals of our current study is to better understand the molecular determinants of these ligands in these different time frames. We have developed an expanded library of compounds, based on previous leads, by combining the pyrimidine system with the di‐picolyl substitution at the 4‐position. To distinguish receptor interactions on nAChRs and related pentameric ligand‐gated ion channels, we employ HEK cells transfected with cDNA's encoding one of three requisite receptor subtypes: α7‐nAChR, α4β2‐nAChR and 5HT 3A R, along with a fluorescent reporter, TN‐XXL. To assess fast activation of lead candidates, we use a Xenopus oocyte system expressing α7‐nAChR. This approach has enabled us to define the molecular determinants of the selective activation of α7‐nAChR's and offer more selective and potent lead candidates with EC 50 's extending to 30nM in the presence of PNU‐120596. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .