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 (alpha4beta2 over alpha2beta3) 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 pEC(50)(alpha4beta2), pEC(50)(alpha2beta3) and p[EC(50)(alpha4beta2)/EC(50)(alpha2beta3)] (pEC(50)(alpha4beta2)pEC(50)(alpha2beta3)) 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 r(2) (r(2)(CV)), 0.924, 0.935 and 0.875 for conventional r(2). Analyses indicated that both the steric and electrostatic factors should be considered in the rational design of more active and selective nAChR agonists.