Design, synthesis, and anticonvulsant effects evaluation of nonimidazole histamine H₃ receptor antagonists/inverse agonists containing triazole moiety

Figures & data

Figure 1. Structures of histamine H₃ receptor ligands with anticonvulsant activity, triazole derivatives with anticonvulsant activity and target compounds 3a-3q designed.

Scheme 1. The synthesis route and conditions for the preparation of compounds 3a-3j.

Scheme 2. The synthesis route and conditions for the preparation of compounds 3k-3q.

Table 1. H₃R antagonistic activity of compounds 3a-3q.

Compounds	R	n	% Antagonism^a		H3R antagonistic activity (IC50, μM)
			100 nM	1 μM
3a			49.85 ± 9.73	223.76 ± 7.56	2.99
3b			13.24 ± 4.83	15.02 ± 4.03	NT^b
3c			32.23 ± 5.69	143.98 ± 16.16	0.553
3d			11.33 ± 5.86	79.4 ± 4.50	NT
3e			9.86 ± 0.87	21.78 ± 3.04	NT
3f			9.96 ± 10.9	24.41 ± 6.30	NT
3g			−0.76 ± 4.87	20.24 ± 7.56	NT
3h			10.56 ± 7.94	239.79 ± 3.17	0.127
3i			5.19 ± 2.06	16.45 ± 1.90	NT
3j			−4.2 ± 3.11	6.12 ± 2.05	NT
3k	Me	1	133.91 ± 8.91	183.54 ± 14.41	0.021
3l	C6H5	1	148.62 ± 4.43	169.04 ± 15.04	0.00781
3m	C6H4(p-Cl)	1	201.12 ± 12.63	203.92 ± 8.44	0.00592
3n	Biphenyl	1	1.03 ± 7.79	3.36 ± 1.27	NT
3o	H	0	45.04 ± 3.61	94.20 ± 2.60	0.25
3p	H	2	25.00 ± 3.95	90.52 ± 5.71	3.44
3q	H	3	1.88 ± 12.38	2.39 ± 13.85	NT
CPX^c			33.96 ± 8.59	63.05 ± 9.33	0.082
PIT^d			54.16 ± 7.33	246.29 ± 21.48	0.51

^a% Antagonism, value represented as mean ± standard deviation of three independent experiments.

^bNT, IC₅₀ was not tested.

^cCPX, an antagonist of H₃R ciproxifan.

^dPIT, an antagonist/inverse agonist of H₃R pitolisant.

Figure 2. Effects of compounds 3a, 3c, 3h, 3k, 3l, and 3m on the level of intracellular cAMP administrated alone.

Figure 3. The H₃R inverse agonistic activity (EC₅₀, μM) of Pitolisant and compound 3m.

Figure 4. The predicted configurations for PIT (A), 3h (B) and 3m (C) binding with H₃R, and their overlying pattern (D).

Figure 5. Effects of H₃R antagonists/inverse agonists 3a-3q (10 mg/kg, i.p.), PIT (10 mg/kg, i.p.) and anticonvulsant drug VPA (300 mg/kg, i.p.) against MES-induced convulsions. Protection for mice was defined as the reduction or abolition of the tonic hind limb extension (THLE) in MES model. Results are showed as mean ± SEM with seven animals in each group. Values are considered significant at *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001 as compared to saline-treated group.

Figure 6. Effects of compounds 3a-3q (10 mg/kg, i.p.), and reference drug PIT (10 mg/kg, i.p.) and VPA (300 mg/kg, i.p.) against PTZ-induced convulsions. Results are showed as mean ± SEM of seven mice in each group. & represent full protection.

Figure 7. Protective effects of compound 3m and reference drug PIT against MES-induced convulsions in different doses. Protection in the test was defined as the reduction or abolition of the THLE in mice. Results were showed as mean ± SEM with seven animals in each group. Values are considered significant at *p < 0.05, **p < 0.01, ***p < 0.001 when compared to saline-treated group. ^&PIT, at 20 mg/kg dose, fully abrogate the THLE for all the tested mice.

Figure 8. Protective effects of compound 3m (10 mg/kg, i.p.) against MES-induced convulsions when pre-treatment of RAMH (10 mg/kg, i.p.). Protection in the test was defined as the reduction or abolition of the THLE in mice. Results are showed as mean ± SEM with seven animals in each group. Values are considered significant at *p < 0.01 as compared to saline-treated group, and ^#p < 0.01 as compared to 3m + RAMH treated group.