Open AccessSynthesis, Pharmacological Characterization, and Structure–Activity Relationships of Noncanonical Selective Agonists for α7 nAChRs
Author(s) -
Gisela Andrea CamachoHernandez,
Clare Stokes,
Brendan M. Duggan,
Katarzyna Kaczanowska,
Stefania Brandao-Araiza,
Lisa Doan,
Roger L. Papke,
Palmer Taylor
Publication year - 2019
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.9b01467
Subject(s) - chemistry , partial agonist , agonist , nicotinic agonist , acetylcholine receptor , xenopus , stereochemistry , structure–activity relationship , pyrimidine , receptor , biophysics , in vitro , biochemistry , biology , gene
A lack of selectivity of classical agonists for the nicotinic acetylcholine receptors (nAChR) has prompted us to identify and develop a distinct scaffold of α7 nAChR-selective ligands. Noncanonical 2,4,6-substituted pyrimidine analogues were framed around compound 40 for a structure-activity relationship study. The new lead compounds activate selectively the α7 nAChRs with EC 50 's between 30 and 140 nM in a PNU-120596-dependent, cell-based calcium influx assay. After characterizing the expanded lead landscape, we ranked the compounds for rapid activation using Xenopus oocytes expressing human α7 nAChR with a two-electrode voltage clamp. This approach enabled us to define the molecular determinants governing rapid activation, agonist potency, and desensitization of α7 nAChRs after exposure to pyrimidine analogues, thereby distinguishing this subclass of noncanonical agonists from previously defined types of agonists (agonists, partial agonists, silent agonists, and ago-PAMs). By NMR, we analyzed p K a values for ionization of lead candidates, demonstrating distinctive modes of interaction for this landscape of ligands.