3D-QSAR and QSSR studies of 3,8-diazabicyclo[4.2.0]octane derivatives as neuronal nicotinic acetylcholine receptors by comparative molecular field analysis (CoMFA)

High subtype selectivity (α4β2 over α2β3) of neuronal nicotinic acetylcholine receptor (nAChR) agonists is critical for the rational design of less toxic drugs used for the treatment of neurodegenerative and psychiatric diseases. Here, three CoMFA models of pEC₅₀(α4β2), pEC₅₀(α2β3) and p[EC₅₀(α4β2)/EC₅₀(α2β3)] (pEC₅₀(α4β2)pEC₅₀(α2β3)) were developed to study the quantitative structure–activity relationship (QSAR) and quantitative structure–selectivity relationship (QSSR) of the 3,8-diazabicyclo[4.2.0]octane derivatives as nAChRs agonists. The parameters of the three models were 0.584, 0.792, and 0.599 for cross-validated r² (r²_CV), 0.924, 0.935 and 0.875 for conventional r². Analyses indicated that both the steric and electrostatic factors should be considered in the rational design of more active and selective nAChR agonists.