Discovery of subtype selective muscarinic receptor antagonists as alternatives to atropine using in silico pharmacophore modeling and virtual screening methods

Adopting in silico pharmacophore modeling, 28 new antimuscarinic compounds were discovered, 9 showing specificity for M1 and low specificity for M3 receptors. The pKi values range from 4.5 to 8.5 nM compared to 8.7 nM for atropine. Key pharmacophore features for subtype selectivity of the most potent molecule were two H-bond acceptors on the oxygen atoms, one ring aromaticity, and aliphatic hydrophobicity of the diethyl moiety.