The synthesis and pharmacological analyses of a number of pyrazolo[3,4-b]quinoline and benzo[b]pyrazolo[4,3-g][1,8]naphthyridine derivatives are reported. We have synthesized the diversely substituted tacrine analogues 1–6, by Friedländer-type reaction of readily available o-amino-1-methyl-pyrazole-dicarbonitriles with cyclohexanone. The biological evaluation showed that pyrazolotacrines 1–6 are inhibitors of Electrophorus electricus acetylcholinesterase (EeAChE), in the micromolar range, and quite selective in respect to serum horse butyrylcholinesterase (eqBuChE) inhibition; the most interesting inhibitor is N-(5-amino-1-methyl-6,7,8,9-tetrahydro-1H-benzo[b]pyrazolo[4,3-g][1,8]naphthyridin-3-yl)acetamide (5) [IC 50 (EeAChE) = 0.069 ± 0.006 μM; IC 50 (eqBuChE) = 6.3 ± 0.6 μM]. Kinetic studies showed that compound 5 is a mixed-type inhibitor of EeAChE (K i = 155 nM). Inhibitor 5 showed a 45% neuroprotection value against rotenone/oligomycin A-induced neuronal death.