-10.03), and 15/17/18 (-9.66 vs. -10.15 vs. -10.44) revealed a superior affinity for the nitrile over chloride and hydrogen in position 5 of the pyridine ring. However, nitrile substituents exhibit a higher topological polar surface area (TPSA) which is ultimately reflected in lower BBB scores. Thus, chloride or hydrogen substituents at position 5 were still added to the set of test compounds to increase the likelihood of brain permeability. The series 10/11 and 16/17 indicated that a methyl group at position 2 may foster higher docking scores. The highest S values were obtained with compounds 13 and 19, which have an aryl scaffold instead of the pyridine ring. A pyridine-fused lactone was introduced in 8 and 14, to account for an increased microsomal stability and affinity. The lactones also displayed higher CNS scores than comparable nicotinates, presumably due to their reduced molecular weight and decreased flexibility. However, the lactones displayed the lowest docking scores, although a beneficial effect on brain permeability can be expected. Variations on the amino linker were made including piperazinyl (6-8), piperidinyl (9-19), or azetidinyl (20-22) residues, corresponding to the selection made by Bach and co-workers from a wide range of different nitrogenheterocycles. A comparison of the S scores for the duplets 6-7, 10 and 12 and 21-22 show that the amino linker exerts a minor influence on the predicted affinity value of the ligand.