Activity and QSAR study of baogongteng A and its derivatives as muscarinic agonists

A new CoMFA model of baogongteng A (BGT-A) and its derivatives with agonistic activity to muscarinic receptors was constructed, discussed, and examined. This model could provide solid basis for designing novel molecules with higher agonistic activity to muscarinic receptors. Baogongteng A (BGT-A), a naturally occurring tropane muscarinic agonist isolated from Chinese medicinal plant, exhibits a bioactive effect different from those of many tropane alkaloids that are muscarinic antagonists. A series of racemic derivatives of BGT-A was synthesized to study the structure–activity relationships (SAR). To explore further the SAR in this series and to ultimately design muscarinic agonists for drug development, a Comparative Molecular Field Analysis (CoMFA) was performed. The values of the leave-one-out cross-validated correlation coefficient q 2 and the conventional correlation coefficient r 2 for the model are 0.613 and 0.965, respectively. The regression analysis of the data indicated that the steric effect of N-substituted group on tropane of analyzed compounds critically affected the agonistic activity to muscarinic receptors.