Synthesis and biological evaluation of 2-fluoro and 3-trifluoromethyl-phenyl-piperazinylalkyl derivatives of 1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione as potential antidepressant agents

Figures & data

Figure 1. General structure of long-chain arylpiperazine (LCAPs) and their representatives of 5-HT_1A and 5-HT₇ receptor ligands.

Figure 2. Chemical structures and inhibitor activity (IC₅₀) of inhibitors of PDE4 and PDE10.

Scheme 1. General method for synthesis of compounds 4–21^a.

Table 1. The binding data and cLog p of compounds 4–21.

				Ki [nM]*
Compound	R	n	R^1	5-HT1A	5-HT7	S†	cLog p
4	2-F	3	–H	11.7 ± 0.8	NA	–	5.67
5	2-F	4	–H	0.6 ± 0.2	508 ± 12.5	0.001	5.34
6	2-F	5	–H	4.8 ± 0.5	119.7 ± 7.3	0.04	4.68
7	2-F	3	–CH3	33 ± 2.0	152 ± 3.5	0.21	5.14
8	2-F	4	–CH3	1.1 ± 0.1	86.5 ± 5.0	0.01	3.81
9	2-F	5	–CH3	2.5 ± 0.2	30.8 ± 3.5	0.08	4.06
10	2-F	3	–C6H5	4.9 ± 0.5	88 ± 4.7	0.05	5.75
11	2-F	4	–C6H5	6.3 ± 0.2	137 ± 4.5	0.04	4.06
12	2-F	5	–C6H5	3.0 ± 0.2	9 ± 1.0	0.33	5.39
13	3-CF3	3	–H	1.8 ± 0.1	NA	–	4.12
14	3-CF3	4	–H	0.2 ± 0.05	136 ± 5.2	0.001	5.75
15	3-CF3	5	–H	0.2 ± 0.04	16 ± 1.2	0.125	5.69
16	3-CF3	3	–CH3	1.1 ± 0.1	NA	–	5.23
17	3-CF3	4	–CH3	0.2 ± 0.05	20 ± 2.2	0.01	5.99
18	3-CF3	5	–CH3	0.6 ± 0.04	10 ± 0.5	0.06	5.73
19	3-CF3	3	–C6H5	0.3 ± 0.03	59.6 ± 4.0	0.005	5.08
20	3-CF3	4	–C6H5	0.1 ± 0.02	10 ± 0.9	0.01	4.72
21	3-CF3	5	–C6H5	0.2 ± 0.04	1 ± 0.2	0.2	5.72

*Data expressed as the mean ± SD of two independent experiments in duplicate.

† 5-HT_1A/5-HT₇ selectivity.

Figure 3. Inhibitor activity (%) against PDE10A for compound 9, theophylline and papaverine in concentration of 10^–5 M and 10^–5.5 M.

Table 2. Inhibition of PDE (%) of compounds 4–21.

	PDE4B		PDE10A
Compound	10^−5	10^−5.5	10^−5	10^−5.5
4	2	0	6	1
5	3	0	6	0
6	1	0	5	0
7	3	0	5	0
8	2	0	4	0
9	6	0	2	0
10	7	0	3	0
11	2	0	9	0
12	3	0	6	0
13	5	0	5	0
14	1	0	0	0
15	0	0	0	0
16	1	0	4	0
17	0	0	3	0
18	1	0	1	0
19	3	0	2	0
20	2	0	3	0
21	4	0	3	0
Theophylline	3	8	2	−5
Papaverine	13	–	78	57
Rolipram	84	75	3	8

Data are expressed as the mean of two independent experiments in duplicate, vehicle control (DMSO).

Figure 4. Antagonist mode (K_b) of the selected compounds for 5-HT_1A receptor.

Figure 5. Antagonist mode (K_b) of selected compounds for the 5-HT₇ receptor.

Table 3. Metabolic stability screen of compounds 9 and 20 in human liver microsomes (HLM) and major metabolites characteristics.

				Metabolites
Comp	[M + H]	Retention time [min]	% of parent comp.	ID	[M + H]^+	Retention time [min]	% of metabolites	Metabolic pathway
9	482	3.93	43	M1	498	3.35	90	Hydroxylation
				M2	320	3.40	10	Dealkylation
20	580	5.28	39	M1	596	4.33	82	Hydroxylation
				M2	352	4.64	18	Dealkylation

Figure 6. The effect of the tested compound and 9 citalopram in the forced swim test (FST) in mice.

Figure 7. The effect of the tested compound 9 and diazepam in the four-plate test in mice.

Figure 8. Binding modes of compound 9 in the site of 5-HT_1A (A) and 5-HT₇ (B) receptors. Amino acid residues engaged in ligand binding (within 4 Å from the ligand atoms) are displayed as sticks, whereas those forming H-bonds (dotted yellow lines) or π–π/CH-π stacking (dotted cyan lines) are represented as thick sticks. Van der Waals molecular surface of the receptor binding site is shown as grid, colored due to electrostatic potential. For the sake of clarity, ECL2 residues were hidden. TMH – transmembrane helix; ECL – extracellular loop.