P.808

Derivatives of 1,3,5-triazine, a new class of 5-HT6 receptor . ligands, can reverse memory impairments in novel object recognition test in rats

M. Jastrzębska-Więsek1, A. Partyka1, M. Więcek2, D. Łażewska2, K. Kamińska2, K. Kieć-Kononowicz2, A. Wesołowska1, J. Handzlik2

1 Jagiellonian University Medical College, Department of Clinical Pharmacy, Cracow, Poland 2 Jagiellonian University Medical College, Department of Technology and Biotechnology of Drugs, Cracow, Poland

Aim:

Obtained pre-clinical results indicate that 5-HT6 receptor antagonism Tab.1. Chemical structures and affinity of investigated adds a unique, and complementary mechanism of action to that of compounds for selected receptors. cholinesterase inhibition and hold promise for the symptomatic treatment of Alzheimer disease (AD). Despite the recently carried out human trials with Ki (nM) cmpd structure and intepirdine have mostly yielded disappointing results as 5-HT6 D2 5-HT1A 5-HT2A 5-HT7 possibility of add-on therapy to treatment in patients with AD, NH2 N N there are still investigated new ligands of 5-HT6 receptor. Hence, a new MST-4 N N O 11 1094 12530 430 11950 series of 1,3,5-triazine derivatives with high affinities and antagonist N H3C properties for 5-HT6 receptor was synthetized and evaluated in novel CH3 CH3 O N object recognition (NOR) test in rats. The influence of investigated N N KMP- N 4247 14160 17170 514 compounds on short-term memory impairment (acquisition phase) after HN NN 87 10 O single scopolamine injection was assessed. NH2 N Cl N N Methods: 838 4954 272 8710 TR-37 NN 28

Animals: NH2 Experiments were performed on male Wistar rats (250-300 g), each experimental group consisted of 6-8 animals. All the experimental NH procedures were approved by the II Local Ethics Commission in Cracow TR-12 22 1946 9453 1757 16790 N N (no 293/2015). 2NH N N N Drugs: Scopolamine (hydrobromide, Tocris, UK); 1,3,5-triazine derivatives NH2 CH3 N N 1192 10220 329 16160 (MST-4, KMP-10, TR-37, TR-12 and KB-61) were synthetized at the KB-61 N N 29 N Department of Technology and Biotechnology of Drugs JU MC H3C

NOR test: The memory impairment was induced by s.c. injection of scopolamine (0.1 mg/kg) 30 min before the first session (T1), while investigated compounds (MST-4, KMP-10, TR-12, TR-37 and KB-61) were given i.p. 60 min before T1. The short-term memory test (T2) was given 1 h after T1 Conclusions session. Than the rats explored the open field for 5 min in the presence of These compounds, as a new group of 5-HT6 receptor one familiar (F) and one novel (N) object. antagonists, showed promising activity on memory processes The time of exploration of F and N object and discrimination index (DI= %N in rats. Therefore further investigations to establish their -%F/100) were evaluated. mechanism of action are necessary.

Statistical analysis: The data were evaluated by a one-way ANOVA followed by Bonferroni’s multiple comparison test, p<0.05 was considered significant.

Fig.1. Effects of investigated compounds on discrimination index in NOR test in rats with scopolamine-impairment memory.

0,8

0,6 ## ### ### ### 0,4 ###

0,2

0 *** ** *** *** *** veh. scop. veh. scop. veh. scop. veh. scop. veh. scop. -0,2 0.1 0.1 0.1 0.1 0.1 + + + +

discrimination index discrimination index + -0,4 scop. MST-4 TR-12 TR-37 scop. KMP-10 KB-61 3 3 3 0.1 3 3 -0,6 scop. scop. scop. -0,8 0.1 0.1 0.1 **p<0.01, ***p<0.001 vs respective vehicle group ##p<0.01, ###p<0.001 vs scopolamine treated group Supported by NCN grant No UMO-2015/17/B/NZ7/02973 Copyright © 2018 Magdalena Jastrzebska-Więsek, m.jastrzebska-wiesek @uj.edu.pl