Figure 1. Chemical structures of tacrine (a) and its derivatives created by introducing substituents on the aromatic core and/or altering the size of the cycloalkyl moiety attached to the aromatic region: 7-MEOTA (b), K1578 (7-chloro-1H,2H,3H-cyclopenta[b]quinolin-9-amine; c), K1592 (1-chloro-6H,7H,8H,9H,10H-cyclohepta[b]quinolin-11-amine; d), K1594 (6-methyl-1,2,3,4-tetrahydroacridin-9-amine; e), and K1599 (7-methoxy-1H,2H,3H-cyclopenta[b]quinolin-9-amine; f). Compounds in this study were used in the form of hydrochloride salts. Figure_2_values. Test results. Morris water maze: scopolamine-induced model of cognitive deficit in the acquisition and reversal phases. The graphs show the effects of K1578 (a), K1592 (b), K1594 (c), and K1599 (d) on escape latency during the acquisition phase, where none of the compounds ameliorated the deficit of spatial learning. The remaining graphs display the effects of K1578 (e), K1592 (f), K1594 (g), and K1599 (h) in the reversal phase, where K1578 (1 mg/kg) and K1599 (at both doses), and marginally K1592 (1 mg/kg; see in the text), mitigated the scopolamine-induced deficit of reversal learning. VEH – vehicle, the numbers in brackets denote the dose applied (mg/kg). Data are presented as the mean + SEM, * vs. VEH, * p < 0.05, ** p < 0.01, *** p < 0.001. n = 6–9 animals per group. Statistical significance was determined using two-way repeated measures ANOVA (a–d) or ANOVA (e, f, h) followed by Dunnett’s multiple comparisons tests. Figure-3_values. Test results. Morris water maze: MK-801-induced model of cognitive deficit in the acquisition phase. The graphs illustrate the effects of the compounds K1578 (a), K1592 (b), K1594 (c), and K1599 (d) on escape latency. Only K1599 (1 mg/kg) ameliorated the MK-801-induced deficit of spatial learning. VEH – vehicle, the numbers in brackets denote the dose (mg/kg). Data are presented as the mean + SEM, * vs. VEH, * p < 0.05, ** p < 0.01. n = 5–7 animals per group. Statistical significance was determined using two-way repeated measures ANOVA followed by Dunnett’s multiple comparisons tests. Figure_4_values. Open field test. The results demonstrate the effects of K1578 (a), K1592 (b), K1594 (c), and K1599 (d) on the distance moved by intact and MK-801-treated animals. VEH – vehicle, the numbers in brackets denote the dose (mg/kg). Data are presented as the mean + SEM, * vs. VEH group of the corresponding phenotype, * p < 0.05, ** p < 0.01, **** p < 0.0001. n = 6–14 animals per group. A significant effect of both factors (treatment and phenotype) was determined using two-way ANOVA, followed by Dunnett’s multiple comparisons tests. Figure-5_values. Acetylcholinesterase activity. The results document the effect of the compounds (1 mg/kg ip) on AChE activity in the hippocampus (a), prefrontal cortex (b), striatum (c), and whole brain sample (d). K1578 and K1599 decreased AChE activity in the striatum. VEH – vehicle. Data are presented as the median with minimum to maximum range, * vs. VEH, *** p < 0.001, **** p < 0.0001. VEH samples AChE enzyme activities reached the following absolute values (a) 15.19 ± 3.09 U/mg protein, (b) 9.810 ± 1.54 U/mg protein, (c) 26.05 ± 3.27 U/mg protein, and (d) 27.38 ± 3.36 U/mg protein. Significance was determined by ANOVA (graphs c, d), followed by Dunnett’s multiple comparisons tests. Figure_6_values. Electrophysiology: Inhibition of GluN1/GluN2A receptors by K1599. Representative whole-cell patch-clamp recordings measured from HEK293 cells expressing the GluN1/GluN2A receptors held at a membrane voltage of −80 mV and +60 mV; 30 μM K1599 was applied as indicated. Results summarizing the relative inhibition induced by 30 µM K1599, measured at the indicated membrane potentials. n ≥ 5 cells per each condition. Table_1. The rats were pseudo-randomly assigned to one of the 18 treatment groups listed in. Each group received two injections: one containing the study compound and another containing either MK-801 or scopolamine, as indicated by the group name. The vehicle group (VEH) received the DMSO vehicle (2.5 mL/kg) and saline. The “scopolamine” and “MK-801” groups received scopolamine or MK-801, respectively, along with the DMSO vehicle (2.5 mL/kg). Table 2. Treatment groups and n in biochemical experiments - AChE activity assay.